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Natural Killer T Cells in Cancer Immunotherapy

Shiny Nair, Madhav V. Dhodapkar

Frontiers in Immunology · 2017 · Review

doi:10.3389/fimmu.2017.01178

Abstract

Natural killer T (NKT) cells are specialized CD1d-restricted T cells that recognize lipid antigens. Following stimulation, NKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. This has impelled the development of NKT cell-targeted immunotherapies for treating cancer. In this review, we provide a brief overview of the stimulatory and regulatory functions of NKT cells in tumor immunity as well as highlight preclinical and clinical studies based on NKT cells. Finally, we discuss future perspectives to better harness the potential of NKT cells for cancer therapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Both innate and adaptive immune systems respond to tumor cells and participate in immune-surveillance against tumor. Defined immune interactions in the context of cancer include recognition of tumor-associated antigens or cues by innate cell populations such as antigen-presenting cells (APCs) [macrophages and dendritic cells (DCs), neutrophils, and natural killer (NK) cells]. Innate immune cells rely on germline encoded pattern recognition receptors to recognize and elicit prompt response against cancer-associated danger signals, and also augment components of the adaptive immune system, composed of antigen-specific B and T cells. One of the key players that link the innate and adaptive immune systems is the natural killer T (NKT) cells. NKT cells are innate-like T lymphocytes that possess ability to quickly respond to antigenic stimulation and rapidly produce copious amounts of cytokines and chemokines. This rapid effect can modulate both innate and adaptive immunity and is important in influencing host immune responses to cancer.

Natural killer T cells are a heterogeneous subset of specialized T cells. These cells exhibit innate cell-like feature of quick response to antigenic exposure in combination with adaptive cell’s precision of antigenic recognition and diverse effector responses. Like conventional T cells, NKT cells undergo thymic development and selection and possess T cell receptor (TCR) to recognize antigens. However, unlike conventional T cells, TCR expressed by NKT cells recognize lipid antigens presented by the conserved and non-polymorphic MHC class 1 like molecule CD1d. In addition to TCRs, NKT cells also possess receptors for cytokines such as IL-12, IL-18, IL-25, and IL-23 similar to innate cells such as NK and innate lymphoid cells. These cytokine receptors can be activated by steady state expression of these inflammatory cytokines even in the absence of TCR signals. Thus, NKT cells can amalgamate signals from both TCR-mediated stimulations and inflammatory cytokines to manifest prompt release of an array of cytokines. These cytokines can in turn modulate different immune cells present in the tumor microenvironment (TME) thus influencing host immune responses to cancer. Their predominant tissue localization and ability to sense cancer-mediated changes in host lipid metabolism or breach in tissue integrity via recognition of endogenous lipids, makes NKT cells an ideal candidate for cancer immunotherapy.

Type I NKT Cells

Broadly, CD1d-restricted NKT cells can be divided into two main subsets based on their TCR diversity and antigen specificities. Type I (invariant) NKT cells, so named because of their limited TCR repertoire, express a semi-invariant TCR (iTCR) α chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) paired with a heterogeneous Vβ chain repertoire (V β 2,7 or 8.2 in mice and V β 11 in humans). The prototypic antigen for type I NKT cells is galactosylceramide (α-GalCer or KRN 7000), which was isolated from a marine sponge as part of an antitumor screen. α-GalCer is a potent activator of type I NKT cells, inducing them to release large amounts of interferon-γ (IFN-γ), which helps activate both CD8+ T cells and APCs. The primary techniques used to study type I NKT cells include staining and identification of type I NKT cells using CD1d-loaded α-GalCer tetramers, administering α-GalCer to activate and study the functions of type I NKT cells and finally using CD1d deficient mice (that lack both type I and type II NKT) or Jα18-deficient mice (lacking only type I NKT). Recent published study reported that Jα18-deficient mice in addition to having deletion in the Traj18 gene segment (essential for type I NKT cell development), also exhibited overall lower TCR repertoire caused by influence of the transgene on rearrangements of several Jα segments upstream Traj18, complicating interpretations of data obtained from the Jα18-deficient mice. To overcome this drawback, a new strain of Jα18-deficient mice lacking type I NKT cells while maintaining the overall TCR repertoire has been generated, which should facilitate future studies on type I NKT cells. Type I NKT cells can be further subdivided based on the surface expression of CD4 and CD8 into CD4+ and CD4−CD8− (DN) subsets and a small fraction of CD8+ cells found in humans. Type I NKT cells are present in different tissues in both mice and humans but at higher frequency in mice. Two very unique characteristics of type I NKT cells are that they possess dual reactivity to both self and foreign lipids, and that even at steady state type I NKT cell have an activated/memory phenotype. Functionally distinct subsets of NKT cells analogous to Th1, Th2, Th17, and TFH subsets of conventional T cells have been described. These subsets express the corresponding cytokines, transcription factors and surface markers of their conventional T cell counterparts. Type I NKT cells have a unique developmental program that is regulated by a number of transcription factors. Transcriptionally, one of the key regulators of type I NKT cell development and activated memory phenotype is the transcription factor promyelocytic leukemia zinc finger (PLZF). In fact, PLZF deficient mice show profound deficiency of type I NKT cells and cytokine production. Other transcription factors that are known to impact type I NKT cell differentiation are c-Myc, RORγt, c-Myb, Elf-1, and Runx1. Furthermore, transcription factors that control conventional T cell differentiation such as Th1 lineage specific transcription factor T-bet and Th2 specific transcription factor GATA-3 can also affect type I NKT cell development. Aside from transcription factors, SLAM-associated protein (SAP) signaling pathway can also selectively control expansion and differentiation of type I NKT cell. Type I NKT cells have been shown to respond to both self and foreign α and β linked glycosphingolipids (GSL), ceramides, and phospholipids. Type I NKT cells have been reported to mostly aid in mounting an effective immune response against tumor.

Type II NKT Cells

Type II NKT cells also called diverse or variant NKT cells, are CD1d-restricted T cells that express more diverse alpha-beta TCRs and do not recognize α-GalCer. Type II NKT cells are major subset in humans with higher frequency as compared to type I NKT cells. Due to absence of specific markers and agonistic antigens to identify all type II NKT cells, characterization of these cells has been challenging. Different methodologies employed to characterize type II NKT cells include, comparing immune responses between Jα18−/− (lacking only type I NKT) and CD1d−/− (lacking both type I and type II NKT) mice, using 24 αβ TCR transgenic mice (that overexpresses Vα3.2/Vβ9 TCR from type II NKT cell hybridoma VIII24), using a Jα18-deficient IL-4 reporter mouse model, staining with antigen-loaded CD1d tetramer and asses binding to type II NKT hybridomas [reviewed in Ref.]. The first major antigen identified for self-glycolipid reactive type II NKT cells in mice was myelin derived glycolipid sulfatide. Subsequently, sulfatide and lysosulfatide reactive CD1d-restricted human type II NKT cells have been reported. Sulfatide specific type II NKT cells predominantly exhibit an oligoclonal TCR repertoire (V α 3/V α 1-J α 7/J α 9 and V β 8.1/V β 3.1-J β 2.7). Other self-glycolipids such as β GlcCer and β GalCer have been shown to activate murine type II NKT cells. Our group recently reported that two major sphingolipids accumulated in Gaucher disease (GD), β-glucosylceramide (β GlcCer) and its deacylated product glucosylsphingosine, are recognized by murine and human type II NKT cells. In an earlier study, we have also shown that lysophosphatidylcholine (LPC), lysophospholipid markedly upregulated in myeloma patients was an antigen for human type II NKT cells. Type II NKT cells can be distinguished from type I NKT cells by their predominance in humans versus mice, TCR binding and distinct antigen specificities. Crystal structures of type II NKT TCR-sulfatide/CD1d complex and type I NKT TCR-α-GalCer/CD1d complex provided insights into the mechanisms by which NKT TCRs recognize antigen. The type I NKT TCR was found to bind α-GalCer/CD1d complex in a rigid, parallel configuration mainly involving the α-chain. The key residues within the CDR2β, CDR3α, and CDR1α loops of the semi-iTCR of type I NKT cells were determined to be involved in the detection of the α-GalCer/CD1d complex. On the other hand, type II NKT TCRs contact their ligands primarily via their CDR3β loop rather than CDR3 α loops in an antiparallel fashion very similar to binding observed in some of the conventional MHC-restricted T cells. Ternary structure of sulfatide-reactive TCR molecules revealed that CDR3 α loop primarily contacted CD1d and the CDR3β determined the specificity of sulfatide antigen. The flexibility in binding of type II NKT TCR to its antigens akin to TCR–peptide–MHC complex resonates with its greater TCR diversity and ability to respond to wide range of ligands. However, despite striking difference between the two subsets, similarities among the two subsets have also been reported. For example, both type I and type II NKT cells are autoreactive and depend on the transcriptional regulator PLZF and SAP for their development. Although, many type II NKT cells seem to have activated/memory phenotype like type I NKT cells, in other studies including ours, a subset of type II NKT cells also displayed naïve T cell phenotype (CD45RA+, CD45RO−, CD62high, and CD69−/low). Type II NKT cell is activated mainly by TCR signaling following recognition of lipid/CD1d complex independent of either TLR signaling or presence of IL-12.

In tumor and autoimmune disease models, type II NKT cells are typically associated with immunosuppression.

How Do NKT Cell Target Tumor Cells?

Several clues exist attributing a significant role of type I NKT cells in mediating protective immune response against tumors. Decreased frequency and function of type I NKT cells in the peripheral blood of different cancer patients is suggestive of their role in effective antitumor immunity. Increased frequency of peripheral blood type I NKT cells in cancer patients predicts a more favorable response to therapy. Furthermore, recent studies found an association between number of tumor-infiltrating NKTs with better clinical outcome. Notably, α-GalCer, the prototypic NKT ligand, was first discovered in a screen for antitumor agents. Many studies using genetic knockouts and murine models of tumor have been useful to discern the role of NKT cells in malignancy. Type I NKT cells can lead to effective antitumor immunity by three mechanisms: (a) direct tumor lysis, (b) recruitment and activation of other innate and adaptive immune cells by initiating Th1 cytokine cascade, and (c) regulating immunosuppressive cells in TME (Figure 1).

Direct Cytotoxicity Against Tumor Cells

Natural killer T cells can eliminate CD1d-expressing transformed cells by direct cytolysis using either perforin, granzyme B, Fas ligand (FasL), or TNF-α-mediated cytotoxic pathways. Tumor cells expressing CD1d are mainly of myelomonocytic and B-cell lineages origin, and very few solid tumors have also been found to be CD1d-positive. Surface expression of CD1d on tumor cells is assumed to directly correlate with NKT cell-mediated cytotoxicity. With higher expression of CD1d, resulting in higher tumor cell lysis and thereby lower metastasis rates, while lack of CD1d expression in tumors leads to their escape from recognition by NKT cells, and tumor progression in some models. These studies postulate that loss or downregulation of surface expression of CD1d favors tumor survival and permits tumor escape from NKT cell-mediated immunosurveillance. This concept is further strengthened by observations that downregulation of CD1d in human breast cancer and multiple Myeloma correlated with increased metastatic potential and disease progression. Similarly, downregulation of CD1d by human papillomavirus in infected cervical epithelial cells was linked to their progression to cervical carcinoma. Another means by which tumor cells escape NKT cell-mediated antitumor response was shown in a mouse model of lymphoma, where shedding of tumor-associated glycolipids was shown to inhibit CD1-mediated presentation to NKT cells. Interestingly, in chronic lymphocytic leukemia (CLL), CD1d expression was found to increase during disease progression, counteracting the suggested role of CD1d as an anti-survival factor in cancer. However, a recent study has shown that higher CD1d expression on CLL cells associated with disease progression actually led to impairment in both function and numbers of type I NKT cells. CD1d independent cytotoxic effect of NKT cells on various hematopoietic tumor cell lines have also been reported. Although, the mechanisms or tumor specific CD1d—glycolipid complex that helps NKT cells recognize and kill only CD1d-positive tumor cells and not normal cells is still enigmatic. Membrane glycolipids especially GSL such as globotriaosyl-ceramide (Gb3Cer/CD77), gangliosides (GD2, GD3, and GM2) have been shown to be overexpressed and altered in a range of cancers compared to normal tissue. Shedding of some of the gangliosides and GSL into the TME have also been reported. Recognition of these overexpressed GSL and gangliosides on the surface of tumor cells may lead to differential recognition and killing of tumor cells by NKT cells.

Cytokine-Mediated Modulations of Effector Cells

In addition to direct tumor lysis, type I NKT cells can activate and recruit both innate and adaptive immune cells, such as DCs, NK cells, B cells, and T cells through rapid secretion of cytokines on activation. This is underscored by the observed increase in NK cells, CD8+ T cells and macrophages among tumor-infiltrating leukocytes brought about by α-GalCer injection. Owing to partially activated state and the presence of preformed cytosolic mRNA for various cytokines, type I NKT cells can rapidly produce broad spectrum of Th1 and Th2 cytokines on activation. The nature and magnitude of the type I NKT cell cytokine response is contingent on a number of variables that include the glycolipid antigen, subsets of NKT, and tissue location. For example, while α-GalCer-activated type I NKT cell primarily elicits an IFN-γ, a synthetic analog of α-GalCer with a truncated lipid chain OCH elicits majorly elicits IL-4 production. Further, DN liver subset of type I NKT was found to confer protection as compared to CD4+ liver subset or IL-4 inducing thymic type I NKT cells in MCA-induced fibrosarcoma model. Type I NKT cells play a crucial role in induction of early immune responses to tumor by influencing DC maturation. Mostly DCs found in TME are immature and inept at activating specific T cells. Maturation and differentiation of DCs is important in shaping the magnitude and polarization of T cell-mediated response. A mutually costimulatory interaction between DC and type I NKT cells ensues following encounter with CD1d/antigen complexes displayed by immature DCs. Ligation of APC-expressed CD40 with upregulated CD40L on type I NKT cells induces DCs’ maturation with higher surface expression of MHC class II, the costimulatory molecules CD40, CD80, CD86, CD70 and the endocytic receptor DEC205 and potent IL-12 production. Sustained IL-12 secretion by mature DCs induces IFN-γ production by NKT cells. Mature DCs reciprocally enhance expression of CD40L and IL-12 receptor on type I NKT cells providing a strong feed forward signal that amplifies IFN-γ responses. Ligation of chemokine receptor CXCR6 on the surface of type I NKT cells by its ligand CXCL16 expressed on APCs can also provide costimulatory signal resulting in robust α-GalCer-induced type I NKT activation. α-GalCer-induced type I NKT cells can provide cognate licensing for cross-priming CD8 alpha + DCs to produce CCL17, which attracts CCR4+CD8+ T cells for subsequent activation. Presence of phenotypic maturation ligands, suitable cytokines (IFN-γ), other functional immunostimulatory factors on type I NKT licensed DC can induce activation of CD8 T cells and their polarization toward antitumor effector function. Release of various cytokines such as IL-2, IL-12, and IFN-γ by type I NKT cells leads to activation and expansion of NK cells into lymphokine-activated killer (LAK) cells. These LAK cells upregulate the effectors or adhesion molecules such as perforin, NKp44, granzymes, FasL, and TRAIL and secrete IFN-γ to adhere and lyse tumor cells. Type I NKT cells can form bidirectional interactions with B cells, wherein B cells can present lipid antigens to type I NKT cells through CD1d and NKT cells can license B cells to effectively prime and activate antitumor CTL responses and can also directly provide B cell help to enhance and sustain humoral response.

Altering the Effects of Immunosuppressive Cells in TME

Tumor-associated macrophages (TAMs) are prominent immunosuppressive immune cells present in the TME. TAMs contribute to tumor progression by enhancing angiogenesis, tumor cell invasion, suppression of NK, and T cell responses. Type I NKT cells were found to co-localize with CD1d-expressing TAMs in neuroblastoma and kill TAMs in an IL-15 and CD1d-restricted manner. Besides TAMs, type I NKTs can alter the effects of CD1d+ myeloid-derived suppressor cells (MDSCs)-mediated immune suppression. MDSCs are heterogeneous population of cells of myeloid origin, which often accumulate during tumor growth and contribute to immune escape and tumor progression. In a model of influenza A viral infection, adoptive transfer of type I NKTs inhibited arginase 1 and nitrous oxide synthase-mediated suppressive activity of MDSCs. The ability of type I NKT cells to abolish the suppressive activity of MDSCs was found to be dependent on CD1d and CD40 interactions. In a tumor model, α-GalCer-loaded MDSCs facilitate conversion of immature MDSCs to mature APCs capable of eliciting cytotoxic NK and T cell immune response against cancer cells. De Santo et al. reported type I NKT cell-mediated reversal of immunosuppressive activity of neutrophils in melanoma, serum amyloid A1 (SAA-1) derived as consequence of tumor-associated inflammation induced differentiation of IL-10-producing neutrophils causing suppression of antigen-specific T cell responses. Conversely, SAA-1 also enhanced CD1d-CD40 dependent interaction between the suppressive neutrophils and type I NKT cells. This crosstalk lead to dephosphorylation of Erk, p38, and phosphatidylinositol-3-OH kinase, which in turn lead to inhibition of IL-10 secretion and promotion of IL-12 production by neutrophils, reinstating the proliferation of antigen-specific CD8+ T cells.

Suppression of Tumor Immunity by Type II NKT Cells

In contrast to the established protective role of type I NKT in most murine tumor models, type II NKT cells have been shown to possess a more suppressive/regulatory role in tumor immunity. Comparison of antitumor response in Jα18-deficient mice (which lack only type I NKT) with CD1d deficient mice (which lack both type I and II NKT cell) revealed that type II NKT cells were responsible for suppression of antitumor responses in several murine tumor models. Furthermore, sulfatide-reactive type II NKT cells was shown to antagonize the protective antitumor immune responses mounted by α-GalCer-stimulated type I NKT cells. Sulfatide activated murine type II NKT cells were reported to inhibit proinflammatory functions of type I NKT cells, conventional T cells and DCs and also induce tolerization of myeloid DCs. A major attribute of type II NKT-mediated suppression of tumor immunity is elevated production of IL-13 and IL-4 cytokines capable of skewing the cytokine response predominantly toward tumor-promoting Th2 type. In a mouse model of transformed recurrent fibrosarcoma, type II NKT cells was shown to suppress cytotoxic T cells through IL-13 production via IL4R and STAT6 axis and also induce MDSCs producing immunosuppressive cytokine TGF-β. Similarly, LPC reactive type II NKT cells have been shown to preferentially produce IL-13 and exhibit immunoregulatory role in myeloma patients. Concentration of LPC, a phospholipid associated with inflammation, was found to be elevated in myeloma sera. Progressive myeloma disease is associated with a decline as well as dysfunctional activation of type I NKT cells and increased frequency of type II NKT cells. The preferential production of IL-13, a cytokine implicated in promoting tumor growth, by LPC specific type II NKT cells suggests their role in disease progression. Recently, we have shown a possible implication of type II NKT cells in the development of B-cell malignancies associated with GD. GD is uniquely associated with increased cancer risk particularly with multiple myeloma. GD is a lysosomal storage disorder caused due to an inherited deficiency of the acidic β-glucosidase enzyme, resulting in marked accumulation of β-glucosylceramide (β GlcCer) and its deacylated product, glucosylsphingosine (LGL1). Increased frequency of LGL1-specific type II NKT cells with reduced frequency of type I NKT cells was observed in murine model and patients of GD. Interestingly, LGL1 reactive type II NKT cells demonstrated follicular helper T cell phenotype and were able to provide help to germinal center B cells to produce lipid-reactive antibodies. In both patients and mice with GD having monoclonal gammopathy, the monoclonal immunoglobulin was found to be reactive to Gaucher lipids. Though studies described earlier hint to pro- and antitumor functional dichotomy between type I and type II NKT, respectively, there are several emerging evidences challenging this paradigm, and the pro/antitumor roles of these cells may be context or activation-dependent. While type I NKT cells have been shown to assume immune-suppressive role in several tumor settings, a recent study showed that CpG-activated type II NKT cells secreted IFN-γ rather than IL-13, which in turn enhanced the activation and function of CD8+ T cells and contributed to the antitumor effect of CpG in the B16 melanoma model.

Preclinical Studies

There are several theoretical advantages for harnessing type I NKT cells against cancer. NKT cell can simultaneously target both MHC positive and negative tumor cells due to ability to activate both antigen-specific CD8+ T cells and NK cells. Second, type I NKT cells show strong adjuvant activity thereby activating both innate and adaptive immune cells. Finally, NKT cells have the ability to convert immature and or tolerogenic DCs found in tumor bed into mature DCs capable of initiating tumor specific CD8+ T cell response. However, major limitations in targeting NKT cell for tumor treatment are the cancer-mediated reversible defect in the number and function of type I NKT cells. Circulating type I NKT cell deficiency leads to decreased proliferation and IFN-γ production by type I NKT cells, consequently skewing immune response to a pro-tumor Th2 cytokine profile. In line with this observation, reduced type I NKT cell frequency was shown to correlate with poor survival, while increased type I NKT cell numbers capable of making IFN-γ have positive prognostic value for survival in cancer patients. To restore the numbers and function of type I NKT cells in cancer patients and murine models, several approaches like administration of α-GalCer either alone or with IL-12, administration of APCs (DC or irradiated tumor cells) with α-GalCer, adoptive transfer of ex vivo expanded and/or activated type I NKT cells, and finally a combination of α-GalCer with antibodies or fusion proteins have been exploited. Data from numerous studies on variety of experimental and spontaneous murine tumor models have shown significant role for NKT cells in launching of powerful antitumor immune responses (Table 1).

Type I NKT cells were shown to be indispensable in mediating IL-12-mediated antitumor effects in low- and moderate-dose IL-12 treatment models. IL-12 was found to activate the NKT cell-mediated lysis of tumor cells and also induce IFN-γ production by type I NKT cells. Administration of soluble α-GalCer leads to activation and expansion of type I NKT cells, creating a milieu of immune-stimulatory cytokines including IFN-γ and costimulatory molecules, resulting in maturation of host APC thus enhancing antitumor T cell response. IFN-γ production by type I NKT cell was found to be pivotal in inducing NK cell activation, proliferation of memory CD4+ and CD8+ T cell effector functions, and inhibiting angiogenesis, all contributing to effective immune response against tumor. One of the major drawbacks of administering soluble free α-GalCer is that it causes type I NKT cell to adopt an anergic state causing unresponsiveness to sequential stimulation with α-GalCer. To circumvent this problem, mice were administrated DCs loaded with either α-GalCer alone or in combination with tumor antigens. α-GalCer-pulsed APCs induced a more prolonged cytokine response as well as powerful antitumor immune response than α-Galcer alone. Another recent immunotherapeutic approach has been to load autologous irradiated tumors, which act as source of tumor antigens with α-GalCer. A big improvement of this approach is CD1d-mediated cross-presentation of endogenous glycolipids and or α-GalCer from tumor cells to NKT cells, leading to DC maturation and consequently effective long-term T cell resistance to the tumor. Another approach involved adoptive transfer of ex vivo expanded and or activated type I NKT cells to restore type I NKT cell numbers in preclinical models of melanoma and lymphoid neoplasms. This approach has been shown to be more effective compared to the i.v. administration of α-GalCer. Finally, combination therapy using monoclonal Abs targeting CD1d alone or in combination with tumor cell death inducing and immunomodulating mAbs has emerged as promising immunotherapeutic candidate against CD1d-negative cancers. Stirnemann and Corgnac et al. attempted to target α-GalCer to tumor site by using constructs consisting of either α-GalCer/CD1d molecules alone or fused to tumor Ag specific scFv fragments in a colon carcinoma and murine melanoma model, respectively, and reported specific tumor localization of type I NKT activating potent antitumor responses compared to α-GalCer alone. Preclinical studies obtained using chimeric antigen receptors (CARs) with engineered type I NKT cells have yielded promising result. CAR-bearing type I NKT cells effectively localized to the tumor sites, eliminating tumor cells, and exhibited potent and specific cytotoxicity against TAMs without producing graft-versus-host disease. Recently, CD62L+CD19−specific CAR-engineered NKT cells have been shown to possess superior therapeutic activity in a B-cell lymphoma model.

Clinical Trials of NKT Cells

Based on the preponderance of data from preclinical mice models, showing that activation of type I NKT cells plays a substantial role in providing protection against tumor growth and metastasis of several tumors, different clinical trials have been initiated to harness NKT cell’s antitumor potential (Table 2). However, while direct administration of soluble α-GalCer in cancer patients was well tolerated, it failed to yield any clinical response. Potential reasons for the low efficacy in human trials could be attributed to insufficient drug delivery, inter-individual variability and very low type I NKT cell numbers at baseline, induction of anergy or regulatory IL-10-producing type I NKT cells. To overcome these limitations of soluble α-GalCer administration and improve NKT-mediated antitumor responses, multiple clinical trials were performed using autologous α-GalCer-pulsed APCs in patients with advanced and recurrent non-small cell lung cancer, head and neck squamous cell carcinoma (Table 2). Different types of APCs and alternative routes to efficiently target activated NKT cells directly to cancer region were optimized to achieve objective antitumor responses. Though promising, this strategy too suffers from certain caveats like the treatment is again dependent on the baseline NKT levels, which are inevitably low in most cancer patients. Second, it is difficult to obtain large number of autologous monocyte-derived DCs (moDCs) from immune suppressed cancer patients and also cumbersome for ex vivo generation of DCs in compliance with good manufacturing practices regulations. Another strategy involves adoptive transfer of in vitro-expanded autologous type I NKT populations. Clinical trials using this approach in non-small cell lung cancer and advanced melanoma do show increase in type I NKT expansion and elevated serum IFN-γ levels in vivo; however, further optimization of the protocols and perhaps combination approaches such as combining with immune checkpoint blockade may be needed to obtain a significant clinical response. Remarkably, combining activated type I NKT cells and α-GalCer-pulsed APCs has been reported to enhance the low antitumor response observed with monotherapy employing either NKT or APCs alone in head and neck squamous cell carcinoma patients. Similarly, combining regimen of α-GalCer-pulsed DCs and the immune-modulatory drug lenalidomide in treating multiple myeloma patients leads to type I NKT expansion with downstream activation of NK, monocytes and decrease in tumor-associated M spikes.

Adoptive Transfer of Type I NKT Cells

Advanced cancer patients with low NKT cell numbers may benefit from development of in vitro methods for generation of large numbers of functional NKT cells which can be further used for adoptive transfers. NKT cells have been generated from CD34+ cells isolated from cord blood using IL-15 and stem cell factor (flt-3 ligand) in liquid culture system. Watarai et al. successfully differentiated murine induced pluripotent stem cells (iPSCs) into functional NKT cells in vitro that secreted large amounts of Th1 cytokine IFN-γ acting as adjuvant and antitumor agent. Recently, protocol to generate human type I NKT cells in vitro from iPSC that are competent in eliciting antitumor activity has been generated. Human type I NKT cells can also be reprogrammed to pluripotency followed by redifferentiation back to type I NKT cells in vitro using an IL-7/IL-15-based cytokine combination. The immunological features of re-differentiated type I NKT cells and their unlimited availability from iPSCs offer a potentially effective immunotherapy against cancer. Functionally mature human NKT cells have been also generated from bone marrow-derived adult hematopoietic stem-progenitor cells by expansion with CD1d-Ig-based artificial-presenting cells. Owing to the feasibility of producing large quantities of competent NKT cells, stem cell-derived type I NKT cells offer a promising strategy for effective anticancer immunotherapy.

Alternate Ligands

As discussed earlier, while α-GalCer is a potent activator of type I NKT cells, α-GalCer suffers from few drawback that limits its use as effective cancer immunotherapeutic. For example, α-GalCer induces anergy in type I NKT cells. This has led to preclinical exploration of several alternate ligands that are now poised to enter the clinic. Synthetic glycolipids or α-GalCer analogs chemically modified to induce more precise and predictable cytokine profile than α-GalCer have been synthesized and tested. These analogs as compared α-GalCer, show superior anticancer immunity in tumor mouse models and therefore hold great potential as an alternative vaccine adjuvant. As compared to α-GalCer, alternative non-glycosidic type I NKT-cell agonist threitol ceramide promoted stronger activation of human and mouse type I NKT cells and stronger antitumor responses in comparison to α-GalCer, making it potential candidate for NKT cell-based clinical trials. Another interesting prospect is encapsulating α-GalCer or other lipids in nanoparticle carriers or liposomes decorated with Abs or ligands to target specific APCs. These approaches have several advantages like slower release of α-GalCer, specific targeting of APC subset, lower amounts of α-GalCer required to activate NKT cells than soluble α-GalCer. Positive therapeutic effect of α-GalCer-loaded octa-arginine modified liposomes was reported in melanoma murine model. Administration of α-GalCer and ovalbumin coencapsulated PLGA nanoparticles provided significant prophylactic and therapeutic responses in mouse melanoma model by enhancing activation and tumor infiltration of the antigen-specific CD8+ T cell.

Combination Approaches

A major limitation of the initial studies targeting NKT cells in cancer is that these studies were conducted using single agent strategies and did not account for blockade of immune checkpoints or other immune-suppressive factors. PD-1:PD-L pathway has been shown to play an important role in mediating αGalCer-induced anergy in NKT cells. Antibody-mediated blockade of PD-1:PD-L interactions at the time of α-GalCer treatment prevent the induction of type I NKT anergy and also enhance the antitumor activities of αGalCer. Therefore, combination of NKT-targeted therapies with PD-1:PD-L blockade should be considered. Synthetic lipopeptide vaccines based on conjugation of MHC-binding peptide epitopes to α-GalCer displayed promising antitumor activity in a melanoma model. The principle behind these vaccines is to simultaneously provide both adjuvant and antigen to the same cell in a controlled fashion. Application of this vaccine technology using different tumor antigens might serve as a novel strategy for diverse malignancies. Combination of type I NKT-targeted DC vaccine with low dose of lenalidomide led to promising clinical activity in myeloma. Therefore, there is an unmet need to pursue combination approaches targeting type I NKT cells to better harness the antitumor properties of type I NKT cells in the clinic.

Concluding Remarks

Natural killer T cells are an important component of the TME and play key roles in regulating antitumor immunity. Although preclinical studies with NKT cell-targeted therapies in murine tumor models have been positive, clinical translation of these results has proven challenging. Translational challenge could be attributed to incomplete knowledge of human NKT subsets. Generation of improved preclinical models that replicate human NKT cell response is needed to gain insights into the cross talk between APCs and NKT subsets and to improve the efficacy of NKT cell-targeting therapies.

Author Contributions

Both SN and MVD participated in conceptualization and drafting of the article as well as critical revision of the article for important intellectual content. Both authors gave final approval of the submitted publication.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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    Godfrey DI Pellicci DG Patel O Kjer-Nielsen L Mccluskey J Rossjohn J Antigen recognition by CD1d-restricted NKT T cell receptors. Semin Immunol (2010 ) 22:61–7.

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    Brennan PJ Brigl M Brenner MB. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nat Rev Immunol (2013 ) 13:101–17.

    Not in our library10.1038/nri3369

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    Salio M Silk JD Jones EY Cerundolo V. Biology of CD1- and MR1-restricted T cells. Annu Rev Immunol (2014 ) 32:323–66.

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    Berzins SP Uldrich AP Pellicci DG Mcnab F Hayakawa Y Smyth MJ Parallels and distinctions between T and NKT cell development in the thymus. Immunol Cell Biol (2004 ) 82:269–75.

    Not in our library10.1111/j.0818-9641.2004.01256.x

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    Godfrey DI Uldrich AP Mccluskey J Rossjohn J Moody DB. The burgeoning family of unconventional T cells. Nat Immunol (2015 ) 16:1114–23.

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    Cohen NR Brennan PJ Shay T Watts GF Brigl M Kang J Shared and distinct transcriptional programs underlie the hybrid nature of iNKT cells. Nat Immunol (2013 ) 14:90–9.

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    Kohlgruber AC Donado CA Lamarche NM Brenner MB Brennan PJ. Activation strategies for invariant natural killer T cells. Immunogenetics (2016 ) 68:649–63.

    Not in our library10.1007/s00251-016-0944-8

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    Fan X Rudensky AY. Hallmarks of tissue-resident lymphocytes. Cell (2016 ) 164:1198–211.

    Not in our library10.1016/j.cell.2016.02.048

  15. 15.

    Kawano T Cui J Koezuka Y Toura I Kaneko Y Motoki K CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science (1997 ) 278:1626–9.

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    Kronenberg M Gapin L The unconventional lifestyle of NKT cells. Nat Rev Immunol (2002 ) 2:557–68.

    Not in our library10.1038/nri854

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    Godfrey DI Hammond KJ Poulton LD Smyth MJ Baxter AG. NKT cells: facts, functions and fallacies. Immunol Today (2000 ) 21:573–83.

    Not in our library10.1016/s0167-5699(00)01735-7

  18. 18.

    Bedel R Matsuda JL Brigl M White J Kappler J Marrack P Lower TCR repertoire diversity in Traj18-deficient mice. Nat Immunol (2012 ) 13:705–6.

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  19. 19.

    Chandra S Zhao M Budelsky A De Mingo Pulido A Day J Fu Z A new mouse strain for the analysis of invariant NKT cell function. Nat Immunol (2015 ) 16:799–800.

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    Bendelac A Killeen N Littman DR Schwartz RH. A subset of CD4+ thymocytes selected by MHC class I molecules. Science (1994 ) 263:1774–8.

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  21. 21.

    Gadola SD Dulphy N Salio M Cerundolo V. Valpha24-JalphaQ-independent, CD1d-restricted recognition of alpha-galactosylceramide by human CD4(+) and CD8alphabeta(+) T lymphocytes. J Immunol (2002 ) 168:5514–20.

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  22. 22.

    Gumperz JE Miyake S Yamamura T Brenner MB. Functionally distinct subsets of CD1d-restricted natural killer T cells revealed by CD1d tetramer staining. J Exp Med (2002 ) 195:625–36.

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    Lee H Hong C Shin J Oh S Jung S Park YK The presence of CD8+ invariant NKT cells in mice. Exp Mol Med (2009 ) 41:866–72.

    Not in our library10.3858/emm.2009.41.12.092

  24. 24.

    Lee PT Benlagha K Teyton L Bendelac A. Distinct functional lineages of human V(alpha)24 natural killer T cells. J Exp Med (2002 ) 195:637–41.

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    Arrenberg P Halder R Kumar V. Cross-regulation between distinct natural killer T cell subsets influences immune response to self and foreign antigens. J Cell Physiol (2009 ) 218:246–50.

    Not in our library10.1002/jcp.21597

  26. 26.

    Jahng AW Maricic I Pedersen B Burdin N Naidenko O Kronenberg M Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis. J Exp Med (2001 ) 194:1789–99.

    Not in our library10.1084/jem.194.12.1789

  27. 27.

    Godfrey DI Stankovic S Baxter AG Raising the NKT cell family. Nat Immunol (2010 ) 11:197–206.

    Not in our library10.1038/ni.1841

  28. 28.

    Wu L Van Kaer L Natural killer T cells and autoimmune disease. Curr Mol Med (2009 ) 9:4–14.

    Not in our library10.2174/156652409787314534

  29. 29.

    Constantinides MG Bendelac A. Transcriptional regulation of the NKT cell lineage. Curr Opin Immunol (2013 ) 25:161–7.

    Not in our library10.1016/j.coi.2013.01.003

  30. 30.

    Coquet JM Chakravarti S Kyparissoudis K Mcnab FW Pitt LA Mckenzie BS Diverse cytokine production by NKT cell subsets and identification of an IL-17-producing CD4-NK1.1- NKT cell population. Proc Natl Acad Sci U S A (2008 ) 105:11287–92.

    Not in our library10.1073/pnas.0801631105

  31. 31.

    Lee YJ Wang H Starrett GJ Phuong V Jameson SC Hogquist KA. Tissue-specific distribution of iNKT cells impacts their cytokine response. Immunity (2015 ) 43:566–78.

    Not in our library10.1016/j.immuni.2015.06.025

  32. 32.

    Das R Sant’Angelo DB Nichols KE. Transcriptional control of invariant NKT cell development. Immunol Rev (2010 ) 238:195–215.

    Not in our library10.1111/j.1600-065x.2010.00962.x

  33. 33.

    Kovalovsky D Uche OU Eladad S Hobbs RM Yi W Alonzo E The BTB-zinc finger transcriptional regulator PLZF controls the development of invariant natural killer T cell effector functions. Nat Immunol (2008 ) 9:1055–64.

    Not in our library10.1038/ni.1641

  34. 34.

    Savage AK Constantinides MG Han J Picard D Martin E Li B The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity (2008 ) 29:391–403.

    Not in our library10.1016/j.immuni.2008.07.011

  35. 35.

    Dose M Sleckman BP Han J Bredemeyer AL Bendelac A Gounari F. Intrathymic proliferation wave essential for Valpha14+ natural killer T cell development depends on c-Myc. Proc Natl Acad Sci U S A (2009 ) 106:8641–6.

    Not in our library10.1073/pnas.0812255106

  36. 36.

    Mycko MP Ferrero I Wilson A Jiang W Bianchi T Trumpp A Selective requirement for c-Myc at an early stage of V(alpha)14i NKT cell development. J Immunol (2009 ) 182:4641–8.

    Not in our library10.4049/jimmunol.0803394

  37. 37.

    Michel ML Mendes-Da-Cruz D Keller AC Lochner M Schneider E Dy M Critical role of ROR-gammat in a new thymic pathway leading to IL-17-producing invariant NKT cell differentiation. Proc Natl Acad Sci U S A (2008 ) 105:19845–50.

    Not in our library10.1073/pnas.0806472105

  38. 38.

    Hu T Simmons A Yuan J Bender TP Alberola-ILA J. The transcription factor c-Myb primes CD4+CD8+ immature thymocytes for selection into the iNKT lineage. Nat Immunol (2010 ) 11:435–41.

    Not in our library10.1038/ni.1865

  39. 39.

    Choi HJ Geng Y Cho H Li S Giri PK Felio K Differential requirements for the ETS transcription factor ELF-1 in the development of NKT cells and NK cells. Blood (2011 ) 117:1880–7.

    Not in our library10.1182/blood-2010-09-309468

  40. 40.

    Egawa T Eberl G Taniuchi I Benlagha K Geissmann F Hennighausen L Genetic evidence supporting selection of the Valpha14i NKT cell lineage from double-positive thymocyte precursors. Immunity (2005 ) 22:705–16.

    Not in our library10.1016/j.immuni.2005.03.011

  41. 41.

    Kim PJ Pai SY Brigl M Besra GS Gumperz J Ho IC. GATA-3 regulates the development and function of invariant NKT cells. J Immunol (2006 ) 177:6650–9.

    Not in our library10.4049/jimmunol.177.10.6650

  42. 42.

    Matsuda JL Zhang Q Ndonye R Richardson SK Howell AR Gapin L. T-bet concomitantly controls migration, survival, and effector functions during the development of Valpha14i NKT cells. Blood (2006 ) 107:2797–805.

    Not in our library10.1182/blood-2005-08-3103

  43. 43.

    Townsend MJ Weinmann AS Matsuda JL Salomon R Farnham PJ Biron CA T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity (2004 ) 20:477–94.

    Not in our library10.1016/s1074-7613(04)00076-7

  44. 44.

    Nichols KE Hom J Gong SY Ganguly A Ma CS Cannons JL Regulation of NKT cell development by SAP, the protein defective in XLP. Nat Med (2005 ) 11:340–5.

    Not in our library10.1038/nm1189

  45. 45.

    Pasquier B Yin L Fondaneche MC Relouzat F Bloch-Queyrat C Lambert N Defective NKT cell development in mice and humans lacking the adapter SAP, the X-linked lymphoproliferative syndrome gene product. J Exp Med (2005 ) 201:695–701.

    Not in our library10.1084/jem.20042432

  46. 46.

    Macho-Fernandez E Brigl M. The extended family of CD1d-restricted NKT cells: sifting through a mixed bag of TCRs, antigens, and functions. Front Immunol (2015 ) 6:362.

    Not in our library10.3389/fimmu.2015.00362

  47. 47.

    Ambrosino E Terabe M Halder RC Peng J Takaku S Miyake S Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis. J Immunol (2007 ) 179:5126–36.

    Not in our library10.4049/jimmunol.179.8.5126

  48. 48.

    Pilones KA Aryankalayil J Demaria S. Invariant NKT cells as novel targets for immunotherapy in solid tumors. Clin Dev Immunol (2012 ) 2012:720803.

    Not in our library10.1155/2012/720803

  49. 49.

    Altman JB Benavides AD Das R Bassiri H. Antitumor responses of invariant natural killer T cells. J Immunol Res (2015 ) 2015:652875.

    Not in our library10.1155/2015/652875

  50. 50.

    Cardell S Tangri S Chan S Kronenberg M Benoist C Mathis D. CD1-restricted CD4+ T cells in major histocompatibility complex class II-deficient mice. J Exp Med (1995 ) 182:993–1004.

    Not in our library10.1084/jem.182.4.993

  51. 51.

    Exley MA Tahir SM Cheng O Shaulov A Joyce R Avigan D A major fraction of human bone marrow lymphocytes are Th2-like CD1d-reactive T cells that can suppress mixed lymphocyte responses. J Immunol (2001 ) 167:5531–4.

    Not in our library10.4049/jimmunol.167.10.5531

  52. 52.

    Blomqvist M Rhost S Teneberg S Lofbom L Osterbye T Brigl M Multiple tissue-specific isoforms of sulfatide activate CD1d-restricted type II NKT cells. Eur J Immunol (2009 ) 39:1726–35.

    Not in our library10.1002/eji.200839001

  53. 53.

    Fuss IJ Joshi B Yang Z Degheidy H Fichtner-Feigl S De Souza H IL-13Ralpha2-bearing, type II NKT cells reactive to sulfatide self-antigen populate the mucosa of ulcerative colitis. Gut (2014 ) 63:1728–36.

    Not in our library10.1136/gutjnl-2013-305671

  54. 54.

    Yang SH Lee JP Jang HR Cha RH Han SS Jeon US Sulfatide-reactive natural killer T cells abrogate ischemia-reperfusion injury. J Am Soc Nephrol (2011 ) 22:1305–14.

    Not in our library10.1681/asn.2010080815

  55. 55.

    Rhost S Sedimbi S Kadri N Cardell SL. Immunomodulatory type II natural killer T lymphocytes in health and disease. Scand J Immunol (2012 ) 76:246–55.

    Not in our library10.1111/j.1365-3083.2012.02750.x

  56. 56.

    Roy KC Maricic I Khurana A Smith TR Halder RC Kumar V. Involvement of secretory and endosomal compartments in presentation of an exogenous self-glycolipid to type II NKT cells. J Immunol (2008 ) 180:2942–50.

    Not in our library10.4049/jimmunol.180.5.2942

  57. 57.

    Nair S Boddupalli CS Verma R Liu J Yang R Pastores GM Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation. Blood (2015 ) 125:1256–71.

    Not in our library10.1182/blood-2014-09-600270

  58. 58.

    Chang DH Deng H Matthews P Krasovsky J Ragupathi G Spisek R Inflammation-associated lysophospholipids as ligands for CD1d-restricted T cells in human cancer. Blood (2008 ) 112:1308–16.

    Not in our library10.1182/blood-2008-04-149831

  59. 59.

    Dhodapkar MV Kumar V. Type II NKT cells and their emerging role in health and disease. J Immunol (2017 ) 198:1015–21.

    Not in our library10.4049/jimmunol.1601399

  60. 60.

    Girardi E Zajonc DM. Molecular basis of lipid antigen presentation by CD1d and recognition by natural killer T cells. Immunol Rev (2012 ) 250:167–79.

    Not in our library10.1111/j.1600-065x.2012.01166.x

  61. 61.

    Pellicci DG Patel O Kjer-Nielsen L Pang SS Sullivan LC Kyparissoudis K Differential recognition of CD1d-alpha-galactosyl ceramide by the V beta 8.2 and V beta 7 semi-invariant NKT T cell receptors. Immunity (2009 ) 31:47–59.

    Not in our library10.1016/j.immuni.2009.04.018

  62. 62.

    Girardi E Maricic I Wang J Mac TT Iyer P Kumar V Type II natural killer T cells use features of both innate-like and conventional T cells to recognize sulfatide self antigens. Nat Immunol (2012 ) 13:851–6.

    Not in our library10.1038/ni.2371

  63. 63.

    Patel O Pellicci DG Gras S Sandoval-Romero ML Uldrich AP Mallevaey T Recognition of CD1d-sulfatide mediated by a type II natural killer T cell antigen receptor. Nat Immunol (2012 ) 13:857–63.

    Not in our library10.1038/ni.2372

  64. 64.

    Zhao J Weng X Bagchi S Wang CR Polyclonal type II natural killer T cells require PLZF and SAP for their development and contribute to CpG-mediated antitumor response. Proc Natl Acad Sci U S A (2014 ) 111:2674–9.

    Not in our library10.1073/pnas.1323845111

  65. 65.

    Marrero I Ware R Kumar V. Type II NKT cells in inflammation, autoimmunity, microbial immunity, and cancer. Front Immunol (2015 ) 6:316.

    Not in our library10.3389/fimmu.2015.00316

  66. 66.

    Arrenberg P Halder R Dai Y Maricic I Kumar V. Oligoclonality and innate-like features in the TCR repertoire of type II NKT cells reactive to a beta-linked self-glycolipid. Proc Natl Acad Sci U S A (2010 ) 107:10984–9.

    Not in our library10.1073/pnas.1000576107

  67. 67.

    Kadri N Korpos E Gupta S Briet C Lofbom L Yagita H CD4(+) type II NKT cells mediate ICOS and programmed death-1-dependent regulation of type 1 diabetes. J Immunol (2012 ) 188:3138–49.

    Not in our library10.4049/jimmunol.1101390

  68. 68.

    Tatituri RV Watts GF Bhowruth V Barton N Rothchild A Hsu FF Recognition of microbial and mammalian phospholipid antigens by NKT cells with diverse TCRs. Proc Natl Acad Sci U S A (2013 ) 110:1827–32.

    Not in our library10.1073/pnas.1220601110

  69. 69.

    Zeissig S Blumberg RS. Primary immunodeficiency associated with defects in CD1 and CD1-restricted T cells. Ann N Y Acad Sci (2012 ) 1250:14–24.

    Not in our library10.1111/j.1749-6632.2011.06380.x

  70. 70.

    Moodycliffe AM Nghiem D Clydesdale G Ullrich SE. Immune suppression and skin cancer development: regulation by NKT cells. Nat Immunol (2000 ) 1:521–5.

    Not in our library10.1038/82782

  71. 71.

    Terabe M Matsui S Noben-Trauth N Chen H Watson C Donaldson DD NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol (2000 ) 1:515–20.

    Not in our library10.1038/82771

  72. 72.

    Terabe M Matsui S Park JM Mamura M Noben-Trauth N Donaldson DD Transforming growth factor-beta production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block cytotoxic T lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med (2003 ) 198:1741–52.

    Not in our library10.1084/jem.20022227

  73. 73.

    Tahir SM Cheng O Shaulov A Koezuka Y Bubley GJ Wilson SB Loss of IFN-gamma production by invariant NK T cells in advanced cancer. J Immunol (2001 ) 167:4046–50.

    Not in our library10.4049/jimmunol.167.7.4046

  74. 74.

    Molling JW Kolgen W Van Der Vliet HJ Boomsma MF Kruizenga H Smorenburg CH Peripheral blood IFN-gamma-secreting Valpha24+Vbeta11+ NKT cell numbers are decreased in cancer patients independent of tumor type or tumor load. Int J Cancer (2005 ) 116:87–93.

    Not in our library10.1002/ijc.20998

  75. 75.

    Yoneda K Morii T Nieda M Tsukaguchi N Amano I Tanaka H The peripheral blood Valpha24+ NKT cell numbers decrease in patients with haematopoietic malignancy. Leuk Res (2005 ) 29:147–52.

    Not in our library10.1016/j.leukres.2004.06.005

  76. 76.

    Yanagisawa K Seino K Ishikawa Y Nozue M Todoroki T Fukao K. Impaired proliferative response of V alpha 24 NKT cells from cancer patients against alpha-galactosylceramide. J Immunol (2002 ) 168:6494–9.

    Not in our library10.4049/jimmunol.168.12.6494

  77. 77.

    Fujii S Shimizu K Klimek V Geller MD Nimer SD Dhodapkar MV Severe and selective deficiency of interferon-gamma-producing invariant natural killer T cells in patients with myelodysplastic syndromes. Br J Haematol (2003 ) 122:617–22.

    Not in our library10.1046/j.1365-2141.2003.04465.x

  78. 78.

    Dhodapkar MV Geller MD Chang DH Shimizu K Fujii S Dhodapkar KM A reversible defect in natural killer T cell function characterizes the progression of premalignant to malignant multiple myeloma. J Exp Med (2003 ) 197:1667–76.

    Not in our library10.1084/jem.20021650

  79. 79.

    Metelitsa LS Wu HW Wang H Yang Y Warsi Z Asgharzadeh S Natural killer T cells infiltrate neuroblastomas expressing the chemokine CCL2. J Exp Med (2004 ) 199:1213–21.

    Not in our library10.1084/jem.20031462

  80. 80.

    Schneiders FL De Bruin RC Van Den Eertwegh AJ Scheper RJ Leemans CR Brakenhoff RH Circulating invariant natural killer T-cell numbers predict outcome in head and neck squamous cell carcinoma: updated analysis with 10-year follow-up. J Clin Oncol (2012 ) 30:567–70.

    Not in our library10.1200/jco.2011.38.8819

  81. 81.

    Tachibana T Onodera H Tsuruyama T Mori A Nagayama S Hiai H Increased intratumor Valpha24-positive natural killer T cells: a prognostic factor for primary colorectal carcinomas. Clin Cancer Res (2005 ) 11:7322–7.

    Not in our library10.1158/1078-0432.ccr-05-0877

  82. 82.

    Natori T Koezuka Y Higa T Novel antitumor and immunostimulatory cerebrosides from the marine sponge Agelas mauritianus. Tetrahedron Lett (1993 ) 34:5591–2.

    Not in our library10.1016/s0040-4039(00)73889-5

  83. 83.

    Shissler SC Bollino DR Tiper IV Bates JP Derakhshandeh R Webb TJ. Immunotherapeutic strategies targeting natural killer T cell responses in cancer. Immunogenetics (2016 ) 68:623–38.

    Not in our library10.1007/s00251-016-0928-8

  84. 84.

    van der Vliet HJ Molling JW Von Blomberg BM Nishi N Kolgen W Van Den Eertwegh AJ The immunoregulatory role of CD1d-restricted natural killer T cells in disease. Clin Immunol (2004 ) 112:8–23.

    Not in our library10.1016/j.clim.2004.03.003

  85. 85.

    Bassiri H Das R Guan P Barrett DM Brennan PJ Banerjee PP iNKT cell cytotoxic responses control T-lymphoma growth in vitro and in vivo. Cancer Immunol Res (2014 ) 2:59–69.

    Not in our library10.1158/2326-6066.cir-13-0104

  86. 86.

    Dao T Mehal WZ Crispe IN. IL-18 augments perforin-dependent cytotoxicity of liver NK-T cells. J Immunol (1998 ) 161:2217–22.

    Not in our library

  87. 87.

    Leite-De-Moraes MC Hameg A Arnould A Machavoine F Koezuka Y Schneider E A distinct IL-18-induced pathway to fully activate NK T lymphocytes independently from TCR engagement. J Immunol (1999 ) 163:5871–6.

    Not in our library

  88. 88.

    Wingender G Krebs P Beutler B Kronenberg M. Antigen-specific cytotoxicity by invariant NKT cells in vivo is CD95/CD178-dependent and is correlated with antigenic potency. J Immunol (2010 ) 185:2721–9.

    Not in our library10.4049/jimmunol.1001018

  89. 89.

    Hagihara M Gansuvd B Ueda Y Tsuchiya T Masui A Tazume K Killing activity of human umbilical cord blood-derived TCRValpha24(+) NKT cells against normal and malignant hematological cells in vitro: a comparative study with NK cells or OKT3 activated T lymphocytes or with adult peripheral blood NKT cells. Cancer Immunol Immunother (2002 ) 51:1–8.

    Not in our library10.1007/s00262-001-0246-2

  90. 90.

    Metelitsa LS. Anti-tumor potential of type-I NKT cells against CD1d-positive and CD1d-negative tumors in humans. Clin Immunol (2011 ) 140:119–29.

    Not in our library10.1016/j.clim.2010.10.005

  91. 91.

    Nowak M Arredouani MS Tun-Kyi A Schmidt-Wolf I Sanda MG Balk SP Defective NKT cell activation by CD1d+ TRAMP prostate tumor cells is corrected by interleukin-12 with alpha-galactosylceramide. PLoS One (2010 ) 5:e11311

    Not in our library10.1371/journal.pone.0011311

  92. 92.

    Hix LM Shi YH Brutkiewicz RR Stein PL Wang CR Zhang M CD1d-expressing breast cancer cells modulate NKT cell-mediated antitumor immunity in a murine model of breast cancer metastasis. PLoS One (2011 ) 6:e20702

    Not in our library10.1371/journal.pone.0020702

  93. 93.

    Chong TW Goh FY Sim MY Huang HH Thike AA Lim WK CD1d expression in renal cell carcinoma is associated with higher relapse rates, poorer cancer-specific and overall survival. J Clin Pathol (2015 ) 68:200–5.

    Not in our library10.1136/jclinpath-2014-202735

  94. 94.

    Dhodapkar KM Cirignano B Chamian F Zagzag D Miller DC Finlay JL Invariant natural killer T cells are preserved in patients with glioma and exhibit antitumor lytic activity following dendritic cell-mediated expansion. Int J Cancer (2004 ) 109:893–9.

    Not in our library10.1002/ijc.20050

  95. 95.

    Liu D Song L Brawley VS Robison N Wei J Gao X Medulloblastoma expresses CD1d and can be targeted for immunotherapy with NKT cells. Clin Immunol (2013 ) 149:55–64.

    Not in our library10.1016/j.clim.2013.06.005

  96. 96.

    Haraguchi K Takahashi T Nakahara F Matsumoto A Kurokawa M Ogawa S CD1d expression level in tumor cells is an important determinant for anti-tumor immunity by natural killer T cells. Leuk Lymphoma (2006 ) 47:2218–23.

    Not in our library10.1080/10428190600682688

  97. 97.

    Fallarini S Paoletti T Orsi Battaglini N Lombardi G. Invariant NKT cells increase drug-induced osteosarcoma cell death. Br J Pharmacol (2012 ) 167:1533–49.

    Not in our library10.1111/j.1476-5381.2012.02108.x

  98. 98.

    Nicol A Nieda M Koezuka Y Porcelli S Suzuki K Tadokoro K Human invariant valpha24+ natural killer T cells activated by alpha-galactosylceramide (KRN7000) have cytotoxic anti-tumour activity through mechanisms distinct from T cells and natural killer cells. Immunology (2000 ) 99:229–34.

    Not in our library10.1046/j.1365-2567.2000.00952.x

  99. 99.

    Spanoudakis E Hu M Naresh K Terpos E Melo V Reid A Regulation of multiple myeloma survival and progression by CD1d. Blood (2009 ) 113:2498–507.

    Not in our library10.1182/blood-2008-06-161281

  100. 100.

    Miura S Kawana K Schust DJ Fujii T Yokoyama T Iwasawa Y CD1d, a sentinel molecule bridging innate and adaptive immunity, is downregulated by the human papillomavirus (HPV) E5 protein: a possible mechanism for immune evasion by HPV. J Virol (2010 ) 84:11614–23.

    Not in our library10.1128/jvi.01053-10

  101. 101.

    Sriram V Cho S Li P O’Donnell PW Dunn C Hayakawa K Inhibition of glycolipid shedding rescues recognition of a CD1+ T cell lymphoma by natural killer T (NKT) cells. Proc Natl Acad Sci U S A (2002 ) 99:8197–202.

    Not in our library10.1073/pnas.122636199

  102. 102.

    Anastasiadis A Kotsianidis I Papadopoulos V Spanoudakis E Margaritis D Christoforidou A CD1d expression as a prognostic marker for chronic lymphocytic leukemia. Leuk Lymphoma (2014 ) 55:320–5.

    Not in our library10.3109/10428194.2013.803222

  103. 103.

    Bojarska-Junak A Hus I Chocholska S Tomczak W Wos J Czubak P CD1d expression is higher in chronic lymphocytic leukemia patients with unfavorable prognosis. Leuk Res (2014 ) 38:435–42.

    Not in our library10.1016/j.leukres.2013.12.015

  104. 104.

    Gorini F Azzimonti L Delfanti G Scarfo L Scielzo C Bertilaccio MT Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis. Blood (2017 ) 129:3440–51.

    Not in our library10.1182/blood-2016-11-751065

  105. 105.

    Kawano T Nakayama T Kamada N Kaneko Y Harada M Ogura N Antitumor cytotoxicity mediated by ligand-activated human V alpha24 NKT cells. Cancer Res (1999 ) 59:5102–5.

    Not in our library

  106. 106.

    Gansuvd B Hagihara M Yu Y Inoue H Ueda Y Tsuchiya T Human umbilical cord blood NK T cells kill tumors by multiple cytotoxic mechanisms. Hum Immunol (2002 ) 63:164–75.

    Not in our library10.1016/s0198-8859(01)00382-2

  107. 107.

    Durrant LG Noble P Spendlove I. Immunology in the clinic review series; focus on cancer: glycolipids as targets for tumour immunotherapy. Clin Exp Immunol (2012 ) 167:206–15.

    Not in our library10.1111/j.1365-2249.2011.04516.x

  108. 108.

    Hakomori S. Tumor malignancy defined by aberrant glycosylation and sphingo(glyco)lipid metabolism. Cancer Res (1996 ) 56:5309–18.

    Not in our library

  109. 109.

    Parekh VV Lalani S Van Kaer L The in vivo response of invariant natural killer T cells to glycolipid antigens. Int Rev Immunol (2007 ) 26:31–48.

    Not in our library10.1080/08830180601070179

  110. 110.

    Nakagawa R Serizawa I Motoki K Sato M Ueno H Iijima R Antitumor activity of alpha-galactosylceramide, KRN7000, in mice with the melanoma B16 hepatic metastasis and immunohistological study of tumor infiltrating cells. Oncol Res (2000 ) 12:51–8.

    Not in our library10.3727/096504001108747521

  111. 111.

    Stetson DB Mohrs M Reinhardt RL Baron JL Wang ZE Gapin L Constitutive cytokine mRNAs mark natural killer (NK) and NK T cells poised for rapid effector function. J Exp Med (2003 ) 198:1069–76.

    Not in our library10.1084/jem.20030630

  112. 112.

    Matsuda JL Mallevaey T Scott-Browne J Gapin L. CD1d-restricted iNKT cells, the ‘Swiss-Army knife’ of the immune system. Curr Opin Immunol (2008 ) 20:358–68.

    Not in our library10.1016/j.coi.2008.03.018

  113. 113.

    Monteiro M Graca L. iNKT cells: innate lymphocytes with a diverse response. Crit Rev Immunol (2014 ) 34:81–90.

    Not in our library10.1615/critrevimmunol.2014010088

  114. 114.

    Sullivan BA Nagarajan NA Wingender G Wang J Scott I Tsuji M Mechanisms for glycolipid antigen-driven cytokine polarization by Valpha14i NKT cells. J Immunol (2010 ) 184:141–53.

    Not in our library10.4049/jimmunol.0902880

  115. 115.

    Crowe NY Coquet JM Berzins SP Kyparissoudis K Keating R Pellicci DG Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med (2005 ) 202:1279–88.

    Not in our library10.1084/jem.20050953

  116. 116.

    Keller CW Freigang S Lunemann JD. Reciprocal crosstalk between dendritic cells and natural killer T cells: mechanisms and therapeutic potential. Front Immunol (2017 ) 8:570.

    Not in our library10.3389/fimmu.2017.00570

  117. 117.
    Immature, Semi-Mature, and Fully Mature Dendritic Cells: Toward a DC-Cancer Cells Interface That Augments Anticancer Immunity · 2013
    No notice
  118. 118.

    de Jong EC Smits HH Kapsenberg ML. Dendritic cell-mediated T cell polarization. Springer Semin Immunopathol (2005 ) 26:289–307.

    Not in our library10.1007/s00281-004-0167-1

  119. 119.

    Kitamura H Iwakabe K Yahata T Nishimura S Ohta A Ohmi Y The natural killer T (NKT) cell ligand alpha-galactosylceramide demonstrates its immunopotentiating effect by inducing interleukin (IL)-12 production by dendritic cells and IL-12 receptor expression on NKT cells. J Exp Med (1999 ) 189:1121–8.

    Not in our library10.1084/jem.189.7.1121

  120. 120.

    Tomura M Yu WG Ahn HJ Yamashita M Yang YF Ono S A novel function of Valpha14+CD4+NKT cells: stimulation of IL-12 production by antigen-presenting cells in the innate immune system. J Immunol (1999 ) 163:93–101.

    Not in our library

  121. 121.

    Shimizu K Hidaka M Kadowaki N Makita N Konishi N Fujimoto K Evaluation of the function of human invariant NKT cells from cancer patients using alpha-galactosylceramide-loaded murine dendritic cells. J Immunol (2006 ) 177:3484–92.

    Not in our library10.4049/jimmunol.177.5.3484

  122. 122.

    Munz C Steinman RM Fujii S. Dendritic cell maturation by innate lymphocytes: coordinated stimulation of innate and adaptive immunity. J Exp Med (2005 ) 202:203–7.

    Not in our library10.1084/jem.20050810

  123. 123.

    Fujii S Shimizu K Hemmi H Fukui M Bonito AJ Chen G Glycolipid alpha-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice. Proc Natl Acad Sci U S A (2006 ) 103:11252–7.

    Not in our library10.1073/pnas.0604812103

  124. 124.

    Fujii S Shimizu K Hemmi H Steinman RM. Innate Valpha14(+) natural killer T cells mature dendritic cells, leading to strong adaptive immunity. Immunol Rev (2007 ) 220:183–98.

    Not in our library10.1111/j.1600-065x.2007.00561.x

  125. 125.

    Hermans IF Silk JD Gileadi U Salio M Mathew B Ritter G Nkt cells enhance CD4+ and CD8+ T cell responses to soluble antigen in vivo through direct interaction with dendritic cells. J Immunol (2003 ) 171:5140–7.

    Not in our library10.4049/jimmunol.171.10.5140

  126. 126.

    Brigl M Tatituri RV Watts GF Bhowruth V Leadbetter EA Barton N Innate and cytokine-driven signals, rather than microbial antigens, dominate in natural killer T cell activation during microbial infection. J Exp Med (2011 ) 208:1163–77.

    Not in our library10.1084/jem.20102555

  127. 127.

    Hayakawa Y Godfrey DI Smyth MJ. Alpha-galactosylceramide: potential immunomodulatory activity and future application. Curr Med Chem (2004 ) 11:241–52.

    Not in our library10.2174/0929867043456115

  128. 128.

    Shimaoka T Seino K Kume N Minami M Nishime C Suematsu M Critical role for Cxc chemokine ligand 16 (SR-PSOX) in Th1 response mediated by NKT cells. J Immunol (2007 ) 179:8172–9.

    Not in our library10.4049/jimmunol.179.12.8172

  129. 129.

    Germanov E Veinotte L Cullen R Chamberlain E Butcher EC Johnston B. Critical role for the chemokine receptor CXCR6 in homeostasis and activation of CD1d-restricted NKT cells. J Immunol (2008 ) 181:81–91.

    Not in our library10.4049/jimmunol.181.1.81

  130. 130.

    Semmling V Lukacs-Kornek V Thaiss CA Quast T Hochheiser K Panzer U Alternative cross-priming through CCL17-CCR4-mediated attraction of CTLs toward NKT cell-licensed DCs. Nat Immunol (2010 ) 11:313–20.

    Not in our library10.1038/ni.1848

  131. 131.

    Gottschalk C Mettke E Kurts C. The role of invariant natural killer T cells in dendritic cell licensing, cross-priming, and memory CD8(+) T cell generation. Front Immunol (2015 ) 6:379.

    Not in our library10.3389/fimmu.2015.00379

  132. 132.

    Vincent MS Leslie DS Gumperz JE Xiong X Grant EP Brenner MB. CD1-dependent dendritic cell instruction. Nat Immunol (2002 ) 3:1163–8.

    Not in our library10.1038/ni851

  133. 133.

    Taraban VY Martin S Attfield KE Glennie MJ Elliott T Elewaut D Invariant NKT cells promote CD8+ cytotoxic T cell responses by inducing CD70 expression on dendritic cells. J Immunol (2008 ) 180:4615–20.

    Not in our library10.4049/jimmunol.180.7.4615

  134. 134.

    Fujii S Shimizu K Smith C Bonifaz L Steinman RM Activation of natural killer T cells by alpha-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein. J Exp Med (2003 ) 198:267–79.

    Not in our library10.1084/jem.20030324

  135. 135.

    Trinchieri G. Natural killer cells wear different hats: effector cells of innate resistance and regulatory cells of adaptive immunity and of hematopoiesis. Semin Immunol (1995 ) 7:83–8.

    Not in our library10.1006/smim.1995.0012

  136. 136.

    Smyth MJ Swann J Kelly JM Cretney E Yokoyama WM Diefenbach A NKG2D recognition and perforin effector function mediate effective cytokine immunotherapy of cancer. J Exp Med (2004 ) 200:1325–35.

    Not in our library10.1084/jem.20041522

  137. 137.

    Chaudhry MS Karadimitris A. Role and regulation of CD1d in normal and pathological B cells. J Immunol (2014 ) 193:4761–8.

    Not in our library10.4049/jimmunol.1401805

  138. 138.

    Chung Y Kim BS Kim YJ Ko HJ Ko SY Kim DH CD1d-restricted T cells license B cells to generate long-lasting cytotoxic antitumor immunity in vivo. Cancer Res (2006 ) 66:6843–50.

    Not in our library10.1158/0008-5472.can-06-0889

  139. 139.

    Kim YJ Ko HJ Kim YS Kim DH Kang S Kim JM alpha-Galactosylceramide-loaded, antigen-expressing B cells prime a wide spectrum of antitumor immunity. Int J Cancer (2008 ) 122:2774–83.

    Not in our library10.1002/ijc.23444

  140. 140.

    Barral P Eckl-Dorna J Harwood NE De Santo C Salio M Illarionov P B cell receptor-mediated uptake of CD1d-restricted antigen augments antibody responses by recruiting invariant NKT cell help in vivo. Proc Natl Acad Sci U S A (2008 ) 105:8345–50.

    Not in our library10.1073/pnas.0802968105

  141. 141.

    Leadbetter EA Brigl M Illarionov P Cohen N Luteran MC Pillai S NK T cells provide lipid antigen-specific cognate help for B cells. Proc Natl Acad Sci U S A (2008 ) 105:8339–44.

    Not in our library10.1073/pnas.0801375105

  142. 142.

    Dellabona P Abrignani S Casorati G. iNKT-cell help to B cells: a cooperative job between innate and adaptive immune responses. Eur J Immunol (2014 ) 44:2230–7.

    Not in our library10.1002/eji.201344399

  143. 143.

    Galli G Nuti S Tavarini S Galli-Stampino L De Lalla C Casorati G CD1d-restricted help to B cells by human invariant natural killer T lymphocytes. J Exp Med (2003 ) 197:1051–7.

    Not in our library10.1084/jem.20021616

  144. 144.

    Mantovani A Marchesi F Malesci A Laghi L Allavena P. Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol (2017 ) 14:399–416.

    Not in our library10.1038/nrclinonc.2016.217

  145. 145.

    Coussens LM Zitvogel L Palucka AK. Neutralizing tumor-promoting chronic inflammation: a magic bullet? Science (2013 ) 339:286–91.

    Not in our library10.1126/science.1232227

  146. 146.

    Qian BZ Pollard JW. Macrophage diversity enhances tumor progression and metastasis. Cell (2010 ) 141:39–51.

    Not in our library10.1016/j.cell.2010.03.014

  147. 147.

    Song L Asgharzadeh S Salo J Engell K Wu HW Sposto R Valpha24-invariant NKT cells mediate antitumor activity via killing of tumor-associated macrophages. J Clin Invest (2009 ) 119:1524–36.

    Not in our library10.1172/jci37869

  148. 148.

    Gabrilovich DI Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol (2009 ) 9:162–74.

    Not in our library10.1038/nri2506

  149. 149.

    De Santo C Salio M Masri SH Lee LY Dong T Speak AO Invariant NKT cells reduce the immunosuppressive activity of influenza A virus-induced myeloid-derived suppressor cells in mice and humans. J Clin Invest (2008 ) 118:4036–48.

    Not in our library10.1172/jci36264

  150. 150.

    Ko HJ Lee JM Kim YJ Kim YS Lee KA Kang CY. Immunosuppressive myeloid-derived suppressor cells can be converted into immunogenic APCs with the help of activated NKT cells: an alternative cell-based antitumor vaccine. J Immunol (2009 ) 182:1818–28.

    Not in our library10.4049/jimmunol.0802430

  151. 151.

    De Santo C Arscott R Booth S Karydis I Jones M Asher R Invariant NKT cells modulate the suppressive activity of IL-10-secreting neutrophils differentiated with serum amyloid A. Nat Immunol (2010 ) 11:1039–46.

    Not in our library10.1038/ni.1942

  152. 152.

    Terabe M Swann J Ambrosino E Sinha P Takaku S Hayakawa Y A nonclassical non-Valpha14Jalpha18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J Exp Med (2005 ) 202:1627–33.

    Not in our library10.1084/jem.20051381

  153. 153.

    Berzofsky JA Terabe M. NKT cells in tumor immunity: opposing subsets define a new immunoregulatory axis. J Immunol (2008 ) 180:3627–35.

    Not in our library10.4049/jimmunol.180.6.3627

  154. 154.

    Berzofsky JA Terabe M. The contrasting roles of NKT cells in tumor immunity. Curr Mol Med (2009 ) 9:667–72.

    Not in our library10.2174/156652409788970706

  155. 155.

    Halder RC Aguilera C Maricic I Kumar V. Type II NKT cell-mediated anergy induction in type I NKT cells prevents inflammatory liver disease. J Clin Invest (2007 ) 117:2302–12.

    Not in our library10.1172/jci31602

  156. 156.

    Mistry PK Taddei T Vom Dahl S Rosenbloom BE. Gaucher disease and malignancy: a model for cancer pathogenesis in an inborn error of metabolism. Crit Rev Oncog (2013 ) 18:235–46.

    Not in our library10.1615/critrevoncog.2013006145

  157. 157.

    Nair S Branagan AR Liu J Boddupalli CS Mistry PK Dhodapkar MV. Clonal immunoglobulin against lysolipids in the origin of myeloma. N Engl J Med (2016 ) 374:555–61.

    Not in our library10.1056/nejmoa1508808

  158. 158.

    Bjordahl RL Gapin L Marrack P Refaeli Y. iNKT cells suppress the CD8+ T cell response to a murine Burkitt’s-like B cell lymphoma. PLoS One (2012 ) 7:e42635.

    Not in our library10.1371/journal.pone.0042635

  159. 159.

    Renukaradhya GJ Sriram V Du W Gervay-Hague J Van Kaer L Brutkiewicz RR. Inhibition of antitumor immunity by invariant natural killer T cells in a T-cell lymphoma model in vivo. Int J Cancer (2006 ) 118:3045–53.

    Not in our library10.1002/ijc.21764

  160. 160.

    Yang W Li H Mayhew E Mellon J Chen PW Niederkorn JY NKT cell exacerbation of liver metastases arising from melanomas transplanted into either the eyes or spleens of mice. Invest Ophthalmol Vis Sci (2011 ) 52:3094–102.

    Not in our library10.1167/iovs.10-7067

  161. 161.

    Pilones KA Kawashima N Yang AM Babb JS Formenti SC Demaria S Invariant natural killer T cells regulate breast cancer response to radiation and CTLA-4 blockade. Clin Cancer Res (2009 ) 15:597–606.

    Not in our library10.1158/1078-0432.ccr-08-1277

  162. 162.

    Zhao J Bagchi S Wang CR Type II natural killer T cells foster the antitumor activity of CpG-oligodeoxynucleotides. Oncoimmunology (2014 ) 3:e28977

    Not in our library10.4161/onci.28977

  163. 163.

    Exley MA Lynch L Varghese B Nowak M Alatrakchi N Balk SP. Developing understanding of the roles of CD1d-restricted T cell subsets in cancer: reversing tumor-induced defects. Clin Immunol (2011 ) 140:184–95.

    Not in our library10.1016/j.clim.2011.04.017

  164. 164.

    Molling JW Langius JA Langendijk JA Leemans CR Bontkes HJ Van Der Vliet HJ Low levels of circulating invariant natural killer T cells predict poor clinical outcome in patients with head and neck squamous cell carcinoma. J Clin Oncol (2007 ) 25:862–8.

    Not in our library10.1200/jco.2006.08.5787

  165. 165.

    Motohashi S Okamoto Y Yoshino I Nakayama T. Anti-tumor immune responses induced by iNKT cell-based immunotherapy for lung cancer and head and neck cancer. Clin Immunol (2011 ) 140:167–76.

    Not in our library10.1016/j.clim.2011.01.009

  166. 166.

    Najera Chuc AE Cervantes LA Retiguin FP Ojeda JV Maldonado ER. Low number of invariant NKT cells is associated with poor survival in acute myeloid leukemia. J Cancer Res Clin Oncol (2012 ) 138:1427–32.

    Not in our library10.1007/s00432-012-1251-x

  167. 167.

    Shaulov A Yue S Wang R Joyce RM Balk SP Kim HT Peripheral blood progenitor cell product contains Th1-biased noninvariant CD1d-reactive natural killer T cells: implications for posttransplant survival. Exp Hematol (2008 ) 36:464–72.

    Not in our library10.1016/j.exphem.2007.12.010

  168. 168.

    Cui J Shin T Kawano T Sato H Kondo E Toura I Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science (1997 ) 278:1623–6.

    Not in our library10.1126/science.278.5343.1623

  169. 169.

    Nakagawa R Motoki K Ueno H Iijima R Nakamura H Kobayashi E Treatment of hepatic metastasis of the colon26 adenocarcinoma with an alpha-galactosylceramide, KRN7000. Cancer Res (1998 ) 58:1202–7.

    Not in our library

  170. 170.
    Natural killer-like nonspecific tumor cell lysis mediated by specific ligand-activated Vα14 NKT cells · 1998
    Not checked
  171. 171.

    Fuji N Ueda Y Fujiwara H Toh T Yoshimura T Yamagishi H. Antitumor effect of alpha-galactosylceramide (KRN7000) on spontaneous hepatic metastases requires endogenous interleukin 12 in the liver. Clin Cancer Res (2000 ) 6:3380–7.

    Not in our library

  172. 172.

    Silk JD Hermans IF Gileadi U Chong TW Shepherd D Salio M Utilizing the adjuvant properties of CD1d-dependent NK T cells in T cell-mediated immunotherapy. J Clin Invest (2004 ) 114:1800–11.

    Not in our library10.1172/jci200422046

  173. 173.

    Nishimura T Watanabe K Yahata T Ushaku L Ando K Kimura M Application of interleukin 12 to antitumor cytokine and gene therapy. Cancer Chemother Pharmacol (1996 ) 38(Suppl):S27–34.

    Not in our library10.1007/s002800051033

  174. 174.

    Nakui M Ohta A Sekimoto M Sato M Iwakabe K Yahata T Potentiation of antitumor effect of NKT cell ligand, alpha-galactosylceramide by combination with IL-12 on lung metastasis of malignant melanoma cells. Clin Exp Metastasis (2000 ) 18:147–53.

    Not in our library10.1023/a:1006715221088

  175. 175.

    Hayakawa Y Takeda K Yagita H Smyth MJ Van Kaer L Okumura K IFN-gamma-mediated inhibition of tumor angiogenesis by natural killer T-cell ligand, alpha-galactosylceramide. Blood (2002 ) 100:1728–33.

    Not in our library

  176. 176.

    Hayakawa Y Rovero S Forni G Smyth MJ. Alpha-galactosylceramide (KRN7000) suppression of chemical- and oncogene-dependent carcinogenesis. Proc Natl Acad Sci U S A (2003 ) 100:9464–9.

    Not in our library10.1073/pnas.1630663100

  177. 177.

    Li J Sun W Subrahmanyam PB Page C Younger KM Tiper IV NKT cell responses to B cell lymphoma. Med Sci (Basel) (2014 ) 2:82–97.

    Not in our library10.3390/medsci2020082

  178. 178.

    Nur H Rao L Frassanito MA De Raeve H Ribatti D Mfopou JK Stimulation of invariant natural killer T cells by alpha-galactosylceramide activates the JAK-STAT pathway in endothelial cells and reduces angiogenesis in the 5T33 multiple myeloma model. Br J Haematol (2014 ) 167:651–63.

    Not in our library10.1111/bjh.13092

  179. 179.

    Kim D Hung CF Wu TC Park YM DNA vaccine with alpha-galactosylceramide at prime phase enhances anti-tumor immunity after boosting with antigen-expressing dendritic cells. Vaccine (2010 ) 28:7297–305.

    Not in our library10.1016/j.vaccine.2010.08.079

  180. 180.

    Toura I Kawano T Akutsu Y Nakayama T Ochiai T Taniguchi M. Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with alpha-galactosylceramide. J Immunol (1999 ) 163:2387–91.

    Not in our library

  181. 181.

    Matsuyoshi H Hirata S Yoshitake Y Motomura Y Fukuma D Kurisaki A Therapeutic effect of alpha-galactosylceramide-loaded dendritic cells genetically engineered to express SLC/CCL21 along with tumor antigen against peritoneally disseminated tumor cells. Cancer Sci (2005 ) 96:889–96.

    Not in our library10.1111/j.1349-7006.2005.00123.x

  182. 182.

    Liu K Idoyaga J Charalambous A Fujii S Bonito A Mordoh J Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells. J Exp Med (2005 ) 202:1507–16.

    Not in our library10.1084/jem.20050956

  183. 183.

    Nagaraj S Ziske C Strehl J Messmer D Sauerbruch T Schmidt-Wolf IG. Dendritic cells pulsed with alpha-galactosylceramide induce anti-tumor immunity against pancreatic cancer in vivo. Int Immunol (2006 ) 18:1279–83.

    Not in our library10.1093/intimm/dxl059

  184. 184.

    Chung Y Qin H Kang CY Kim S Kwak LW Dong C. An NKT-mediated autologous vaccine generates CD4 T-cell dependent potent antilymphoma immunity. Blood (2007 ) 110:2013–9.

    Not in our library10.1182/blood-2006-12-061309

  185. 185.

    Shimizu K Goto A Fukui M Taniguchi M Fujii S. Tumor cells loaded with alpha-galactosylceramide induce innate NKT and NK cell-dependent resistance to tumor implantation in mice. J Immunol (2007 ) 178:2853–61.

    Not in our library10.4049/jimmunol.178.5.2853

  186. 186.

    Petersen TR Sika-Paotonu D Knight DA Dickgreber N Farrand KJ Ronchese F Potent anti-tumor responses to immunization with dendritic cells loaded with tumor tissue and an NKT cell ligand. Immunol Cell Biol (2010 ) 88:596–604.

    Not in our library10.1038/icb.2010.9

  187. 187.

    Mattarollo SR West AC Steegh K Duret H Paget C Martin B NKT cell adjuvant-based tumor vaccine for treatment of myc oncogene-driven mouse B-cell lymphoma. Blood (2012 ) 120:3019–29.

    Not in our library10.1182/blood-2012-04-426643

  188. 188.

    Hong S Lee H Jung K Lee SM Lee SJ Jun HJ Tumor cells loaded with alpha-galactosylceramide promote therapeutic NKT-dependent anti-tumor immunity in multiple myeloma. Immunol Lett (2013 ) 156:132–9.

    Not in our library10.1016/j.imlet.2013.10.002

  189. 189.

    Macho-Fernandez E Cruz LJ Ghinnagow R Fontaine J Bialecki E Frisch B Targeted delivery of alpha-galactosylceramide to CD8alpha+ dendritic cells optimizes type I NKT cell-based antitumor responses. J Immunol (2014 ) 193:961–9.

    Not in our library10.4049/jimmunol.1303029

  190. 190.

    Gibbins JD Ancelet LR Weinkove R Compton BJ Painter GF Petersen TR An autologous leukemia cell vaccine prevents murine acute leukemia relapse after cytarabine treatment. Blood (2014 ) 124:2953–63.

    Not in our library10.1182/blood-2014-04-568956

  191. 191.

    Veinotte L Gebremeskel S Johnston B CXCL16-positive dendritic cells enhance invariant natural killer T cell-dependent IFNgamma production and tumor control. Oncoimmunology (2016 ) 5:e1160979

    Not in our library10.1080/2162402x.2016.1160979

  192. 192.

    Dong T Yi T Yang M Lin S Li W Xu X Co-operation of alpha-galactosylceramide-loaded tumour cells and TLR9 agonists induce potent anti-tumour responses in a murine colon cancer model. Biochem J (2016 ) 473:7–19.

    Not in our library10.1042/bj20150129

  193. 193.

    Escriba-Garcia L Alvarez-Fernandez C Tellez-Gabriel M Sierra J Briones J Dendritic cells combined with tumor cells and alpha-galactosylceramide induce a potent, therapeutic and NK-cell dependent antitumor immunity in B cell lymphoma. J Transl Med (2017 ) 15:115

    Not in our library10.1186/s12967-017-1219-3

  194. 194.

    Shin T Nakayama T Akutsu Y Motohashi S Shibata Y Harada M Inhibition of tumor metastasis by adoptive transfer of IL-12-activated Valpha14 NKT cells. Int J Cancer (2001 ) 91:523–8.

    Not in our library10.1002/1097-0215(20010215)91:4<523::aid-ijc1087>3.0.co;2-l

  195. 195.

    Scheffold C Kornacker M Scheffold YC Contag CH Negrin RS. Visualization of effective tumor targeting by CD8+ natural killer T cells redirected with bispecific antibody F(ab’)(2)HER2xCD3. Cancer Res (2002 ) 62:5785–91.

    Not in our library

  196. 196.

    Bagnara D Ibatici A Corselli M Sessarego N Tenca C De Santanna A Adoptive immunotherapy mediated by ex vivo expanded natural killer T cells against CD1d-expressing lymphoid neoplasms. Haematologica (2009 ) 94:967–74.

    Not in our library10.3324/haematol.2008.001339

  197. 197.

    Payne KK Keim RC Graham L Idowu MO Wan W Wang XY Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells. J Leukoc Biol (2016 ) 100:625–35.

    Not in our library10.1189/jlb.5a1215-580r

  198. 198.

    Teng MW Yue S Sharkey J Exley MA Smyth MJ CD1d activation and blockade: a new antitumor strategy. J Immunol (2009 ) 182:3366–71.

    Not in our library10.4049/jimmunol.0802964

  199. 199.

    Teng MW Sharkey J Mclaughlin NM Exley MA Smyth MJ CD1d-based combination therapy eradicates established tumors in mice. J Immunol (2009 ) 183:1911–20.

    Not in our library10.4049/jimmunol.0900796

  200. 200.

    Stirnemann K Romero JF Baldi L Robert B Cesson V Besra GS Sustained activation and tumor targeting of NKT cells using a CD1d-anti-HER2-scFv fusion protein induce antitumor effects in mice. J Clin Invest (2008 ) 118:994–1005.

    Not in our library10.1172/jci33249

  201. 201.

    Corgnac S Perret R Derre L Zhang L Stirnemann K Zauderer M CD1d-antibody fusion proteins target iNKT cells to the tumor and trigger long-term therapeutic responses. Cancer Immunol Immunother (2013 ) 62:747–60.

    Not in our library10.1007/s00262-012-1381-7

  202. 202.

    Heczey A Liu D Tian G Courtney AN Wei J Marinova E Invariant NKT cells with chimeric antigen receptor provide a novel platform for safe and effective cancer immunotherapy. Blood (2014 ) 124:2824–33.

    Not in our library10.1182/blood-2013-11-541235

  203. 203.

    Tian G Courtney AN Jena B Heczey A Liu D Marinova E CD62L+ NKT cells have prolonged persistence and antitumor activity in vivo. J Clin Invest (2016 ) 126:2341–55.

    Not in our library10.1172/jci83476

  204. 204.

    Smyth MJ Crowe NY Hayakawa Y Takeda K Yagita H Godfrey DI. NKT cells – conductors of tumor immunity? Curr Opin Immunol (2002 ) 14:165–71.

    Not in our library10.1016/s0952-7915(02)00316-3

  205. 205.

    Parekh VV Wilson MT Olivares-Villagomez D Singh AK Wu L Wang CR Glycolipid antigen induces long-term natural killer T cell anergy in mice. J Clin Invest (2005 ) 115:2572–83.

    Not in our library10.1172/jci24762

  206. 206.

    Fujii S Shimizu K Kronenberg M Steinman RM. Prolonged IFN-gamma-producing NKT response induced with alpha-galactosylceramide-loaded DCs. Nat Immunol (2002 ) 3:867–74.

    Not in our library10.1038/ni827

  207. 207.

    Nishimura T Kitamura H Iwakabe K Yahata T Ohta A Sato M The interface between innate and acquired immunity: glycolipid antigen presentation by CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigen-specific cytotoxic T lymphocytes. Int Immunol (2000 ) 12:987–94.

    Not in our library10.1093/intimm/12.7.987

  208. 208.

    Exley MA Friedlander P Alatrakchi N Vriend L Yue S Sasada T Adoptive transfer of invariant NKT cells as immunotherapy for advanced melanoma: a phase I clinical trial. Clin Cancer Res (2017 ) 23:3510–9.

    Not in our library10.1158/1078-0432.ccr-16-0600

  209. 209.

    Giaccone G Punt CJ Ando Y Ruijter R Nishi N Peters M A phase I study of the natural killer T-cell ligand alpha-galactosylceramide (KRN7000) in patients with solid tumors. Clin Cancer Res (2002 ) 8:3702–9.

    Not in our library

  210. 210.

    Sag D Krause P Hedrick CC Kronenberg M Wingender G. IL-10-producing NKT10 cells are a distinct regulatory invariant NKT cell subset. J Clin Invest (2014 ) 124:3725–40.

    Not in our library10.1172/jci72308

  211. 211.

    Sullivan BA Kronenberg M Activation or anergy: NKT cells are stunned by alpha-galactosylceramide. J Clin Invest (2005 ) 115:2328–9.

    Not in our library10.1172/jci26297

  212. 212.

    Kunii N Horiguchi S Motohashi S Yamamoto H Ueno N Yamamoto S Combination therapy of in vitro-expanded natural killer T cells and alpha-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and neck carcinoma. Cancer Sci (2009 ) 100:1092–8.

    Not in our library10.1111/j.1349-7006.2009.01135.x

  213. 213.

    Yamasaki K Horiguchi S Kurosaki M Kunii N Nagato K Hanaoka H Induction of NKT cell-specific immune responses in cancer tissues after NKT cell-targeted adoptive immunotherapy. Clin Immunol (2011 ) 138:255–65.

    Not in our library10.1016/j.clim.2010.11.014

  214. 214.

    Richter J Neparidze N Zhang L Nair S Monesmith T Sundaram R Clinical regressions and broad immune activation following combination therapy targeting human NKT cells in myeloma. Blood (2013 ) 121:423–30.

    Not in our library10.1182/blood-2012-06-435503

  215. 215.

    Nieda M Okai M Tazbirkova A Lin H Yamaura A Ide K Therapeutic activation of Valpha24+Vbeta11+ NKT cells in human subjects results in highly coordinated secondary activation of acquired and innate immunity. Blood (2004 ) 103:383–9.

    Not in our library10.1182/blood-2003-04-1155

  216. 216.

    Ishikawa A Motohashi S Ishikawa E Fuchida H Higashino K Otsuji M A phase I study of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res (2005 ) 11:1910–7.

    Not in our library10.1158/1078-0432.ccr-04-1453

  217. 217.

    Motohashi S Nagato K Kunii N Yamamoto H Yamasaki K Okita K A phase I-II study of alpha-galactosylceramide-pulsed IL-2/GM-CSF-cultured peripheral blood mononuclear cells in patients with advanced and recurrent non-small cell lung cancer. J Immunol (2009 ) 182:2492–501.

    Not in our library10.4049/jimmunol.0800126

  218. 218.

    Nicol AJ Tazbirkova A Nieda M Comparison of clinical and immunological effects of intravenous and intradermal administration of alpha-galactosylceramide (KRN7000)-pulsed dendritic cells. Clin Cancer Res (2011 ) 17:5140–51.

    Not in our library10.1158/1078-0432.ccr-10-3105

  219. 219.

    Nagato K Motohashi S Ishibashi F Okita K Yamasaki K Moriya Y Accumulation of activated invariant natural killer T cells in the tumor microenvironment after alpha-galactosylceramide-pulsed antigen presenting cells. J Clin Immunol (2012 ) 32:1071–81.

    Not in our library10.1007/s10875-012-9697-9

  220. 220.

    Uchida T Horiguchi S Tanaka Y Yamamoto H Kunii N Motohashi S Phase I study of alpha-galactosylceramide-pulsed antigen presenting cells administration to the nasal submucosa in unresectable or recurrent head and neck cancer. Cancer Immunol Immunother (2008 ) 57:337–45.

    Not in our library10.1007/s00262-007-0373-5

  221. 221.

    Chang DH Osman K Connolly J Kukreja A Krasovsky J Pack M Sustained expansion of NKT cells and antigen-specific T cells after injection of alpha-galactosyl-ceramide loaded mature dendritic cells in cancer patients. J Exp Med (2005 ) 201:1503–17.

    Not in our library10.1084/jem.20042592

  222. 222.

    Motohashi S Ishikawa A Ishikawa E Otsuji M Iizasa T Hanaoka H A phase I study of in vitro expanded natural killer T cells in patients with advanced and recurrent non-small cell lung cancer. Clin Cancer Res (2006 ) 12:6079–86.

    Not in our library10.1158/1078-0432.ccr-06-0114

  223. 223.

    Watarai H Fujii S Yamada D Rybouchkin A Sakata S Nagata Y Murine induced pluripotent stem cells can be derived from and differentiate into natural killer T cells. J Clin Invest (2010 ) 120:2610–8.

    Not in our library10.1172/jci42027

  224. 224.

    Yamada D Iyoda T Vizcardo R Shimizu K Sato Y Endo TA Efficient regeneration of human Valpha24+ invariant natural killer T cells and their anti-tumor activity in vivo. Stem Cells (2016 ) 34:2852–60.

    Not in our library10.1002/stem.2465

  225. 225.

    Kitayama S Zhang R Liu TY Ueda N Iriguchi S Yasui Y Cellular adjuvant properties, direct cytotoxicity of re-differentiated Valpha24 invariant NKT-like cells from human induced pluripotent stem cells. Stem Cell Reports (2016 ) 6:213–27.

    Not in our library10.1016/j.stemcr.2016.01.005

  226. 226.

    Sun W Wang Y East JE Kimball AS Tkaczuk K Kesmodel S Invariant natural killer T cells generated from human adult hematopoietic stem-progenitor cells are poly-functional. Cytokine (2015 ) 72:48–57.

    Not in our library10.1016/j.cyto.2014.12.009

  227. 227.

    Carreno LJ Saavedra-Avila NA Porcelli SA. Synthetic glycolipid activators of natural killer T cells as immunotherapeutic agents. Clin Transl Immunology (2016 ) 5:e69.

    Not in our library10.1038/cti.2016.14

  228. 228.

    Venkataswamy MM Porcelli SA. Lipid and glycolipid antigens of CD1d-restricted natural killer T cells. Semin Immunol (2010 ) 22:68–78.

    Not in our library10.1016/j.smim.2009.10.003

  229. 229.

    Carreno LJ Kharkwal SS Porcelli SA Optimizing NKT cell ligands as vaccine adjuvants. Immunotherapy (2014 ) 6:309–20.

    Not in our library10.2217/imt.13.175

  230. 230.

    Jukes JP Gileadi U Ghadbane H Yu TF Shepherd D Cox LR Non-glycosidic compounds can stimulate both human and mouse iNKT cells. Eur J Immunol (2016 ) 46:1224–34.

    Not in our library10.1002/eji.201546114

  231. 231.

    Faveeuw C Trottein F. Optimization of natural killer T cell-mediated immunotherapy in cancer using cell-based and nanovector vaccines. Cancer Res (2014 ) 74:1632–8.

    Not in our library10.1158/0008-5472.can-13-3504

  232. 232.

    Nakamura T Moriguchi R Kogure K Harashima H. Incorporation of polyinosine-polycytidylic acid enhances cytotoxic T cell activity and antitumor effects by octaarginine-modified liposomes encapsulating antigen, but not by octaarginine-modified antigen complex. Int J Pharm (2013 ) 441:476–81.

    Not in our library10.1016/j.ijpharm.2012.11.006

  233. 233.

    Dolen Y Kreutz M Gileadi U Tel J Vasaturo A Van Dinther EA Co-delivery of PLGA encapsulated invariant NKT cell agonist with antigenic protein induce strong T cell-mediated antitumor immune responses. Oncoimmunology (2016 ) 5:e1068493

    Not in our library10.1080/2162402x.2015.1068493

  234. 234.

    Parekh VV Lalani S Kim S Halder R Azuma M Yagita H PD-1/PD-L blockade prevents anergy induction and enhances the anti-tumor activities of glycolipid-activated invariant NKT cells. J Immunol (2009 ) 182:2816–26.

    Not in our library10.4049/jimmunol.0803648

  235. 235.

    Compton BJ Tang CW Johnston KA Osmond TL Hayman CM Larsen DS Synthesis and activity of 6"-deoxy-6"-thio-alpha-GalCer and peptide conjugates. Org Lett (2015 ) 17:5954–7.

    Not in our library10.1021/acs.orglett.5b02836

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