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Immune Evasion in Pancreatic Cancer: From Mechanisms to Therapy

Neus Martinez-Bosch, Judith Vinaixa, Pilar Navarro

Cancers · 2018 · Review · CC BY

doi:10.20944/preprints201712.0014.v1

Abstract

Pancreatic ductal adenocarcinoma (PDA), the most frequent type of pancreatic cancer, remains one of the most challenging problems for the biomedical and clinical fields, with abysmal survival rates and poor therapy efficiency. Desmoplasia, which is abundant in PDA, can be blamed for much of the mechanisms behind poor drug performance, as it is the main source of the cytokines and chemokines that orchestrate rapid and silent tumor progression to allow tumor cells to be isolated into an extensive fibrotic reaction, which results in inefficient drug delivery. However, since immunotherapy was proclaimed as the breakthrough of the year in 2013, the focus on the stroma of pancreatic cancer has interestingly moved from activated fibroblasts to the immune compartment, trying to understand the immunosuppressive factors that play a part in the strong immune evasion that characterizes PDA. The PDA microenvironment is highly immunosuppressive and is basically composed of T regulatory cells (Tregs), tumor-associated macrophages (TAMs), and myeloid-derived suppressive cells (MDSCs), which block CD8+ T-cell duties in tumor recognition and clearance. Interestingly, preclinical data have highlighted the importance of this immune evasion as the source of resistance to single checkpoint immunotherapies and cancer vaccines and point at pathways that inhibit the immune attack as a key to solve the therapy puzzle. Here, we will discuss the molecular mechanisms involved in PDA immune escape as well as the state of the art of the PDA immunotherapy.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 21, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

The immune system plays a key role in both the positive and negative regulation of tumor development and progression, and crosstalk between cancer cells and immune cells has been incorporated into the list of major hallmarks of cancer. While immune surveillance is the first filter to identify and eliminate aberrant or malignant cells, some tumor cells have developed numerous strategies to avoid recognition by the host immune cells, allowing them to escape from immune control and continue cancer progression. Different mechanisms are involved in tumor immune evasion. First, cancer cells can decrease immune recognition by downregulating antigen presentation pathways, like the major histocompatibility complex (MHC) I proteins, TAP (transporter associated with antigen processing) protein and latent membrane proteins (LMP2 and LMP7). Moreover, genetic instability of tumors and constant cell division can result in the loss of tumor antigens recognized by effector T-cells (CD8+ or CD4+ T-cells). These changes in the immunogenicity of cancer cells leading to immune-resistant clones have been called tumor “immunoediting”. Second, tumor cells and other cells from the tumor microenvironment can promote an immune privilege status by secretion of immunosuppressive cytokines—such as IL-1, IL-6, IL-10, TGFβ, TNFα, or VEGF—or modulation of the expression of immunoregulatory molecules to induce T cell anergy or tolerance, such as the immune checkpoints molecules of the B7 family (PD1/PDL1, B7-1, B7-2/CTLA4, B7-H4), A2AR, LAG-3, galectin-9/TIM-3, IDO, and VISTA. Finally, overexpression of STAT3 or BCL-2 by tumor cells increases their resistance to apoptosis and also contributes to immune escape. Altogether, these mechanisms orchestrate an immunosuppressive cancer microenvironment through inhibition of immune cells involved in tumor rejection—CD4+/CD8+ T lymphocytes and natural killer (NK) cells—together with the recruitment and/or activation of immunosuppressive cells, like CD4+CD25+FoxP3+ T regulatory cells (Tregs), myeloid-derived suppressor cells (MDSCs) and anti-inflammatory M2 macrophages. Although there is considerable knowledge about these immune evasion strategies and how to face them using immunotherapy in several tumor types (such as in melanomas, lung cancer, or lymphomas), little is known about pancreatic cancer. Here, we review the molecular mechanisms involved in the immunosuppressive nature of pancreatic ductal adenocarcinoma (PDA) and the current progress that has been made in immunology-based therapy against this dismal disease.

2. PDA Tumor Heterogeneity and Immune Responses

Genomic analyses have revealed the biological complexity and high tumor heterogeneity of PDA. Whole-exome and whole-genome sequencing studies have revealed a high number of somatic copy number alterations and mutations in pancreatic cancer, leading to altered expression of key oncogenes and tumor suppressor genes, such as KRAS, TP53, SMAD4, and CDKN2A. More recent studies from the Australian Pancreatic Cancer Genome Initiative/International Cancer Genome Consortium and from The Cancer Genome Atlas (TCGA) network have validated these results and have also added a long list of other less-frequently mutated genes, confirming the complex molecular landscape of pancreatic cancer. These gene expression analyses have allowed PDA patients to be classified according to their molecular signatures into different subtypes that associate with histopathological hallmarks and prognosis, providing new avenues for personalized medicine. The most recent subcategories proposed for PDA include four subtypes: (1) pancreatic progenitor or classical PDA, which express early pancreatic development genes (i.e., PDX1, FOXA2/3, HES1); (2) squamous or quasimesenchymal tumors, which have increased TP53 mutations, upregulated TP63ΔN and activated TGF-β signaling and MYC pathways and a poor prognosis; (3) aberrantly differentiated endocrine/exocrine tumors, which overexpress genes involved in KRAS activation and exocrine (NR5A, RBPJL) and endocrine (NEUROD1, NKX2-2) markers; and (4) immunogenic PDA. The last subtype has molecular similarities to classical PDA, but also expresses genes associated to immune phenotypes, such as Toll-like receptors, antigen presentation molecules and genes related to infiltrating B and T cells, both T-cytotoxic (CD8+) and Tregs. Moreover, these tumors also show upregulation of the immune checkpoint molecules CTLA4 and PD1, suggesting that the immunogenic PDA subtype may be sensitive to immunotherapy.

However, most pancreatic tumors do not belong to the immunogenic subtype, and PDA is therefore generally described as a poorly immunogenic tumor. The PDA immunosuppressive microenvironment is mainly composed of Tregs, macrophages and MDSCs, which block the anti-tumoral activity of effector CD4+ and CD8+ T-cells. These immunosuppressive cells are already present in preneoplastic lesions (PanINs), indicating that they may be key players in tumor initiation. The important role of Tregs in PDA has been shown in a murine model, in which disruption of these cells correlated with tumor growth inhibition. Tumor-associated macrophages (TAMs) also play important functions in pancreatic tumor chronic inflammation, progression and metastasis. TAMs express chemokine (C-C motif) receptor type 2 (CCR2), a chemokine receptor that interacts with chemokine (C-C motif) ligand 2 (CCL2) and exerts a pro-tumoral role mediating tumor proliferation, angiogenesis, and chemotaxis of immune suppressive cells to the tumor stroma.

PDA also contributes to immunosuppression by upregulation of negative T cell co-stimulatory molecules. In this regard, PDL1 and PDL2 are overexpressed in PDA patients and correlate with reduced tumor-infiltrating leukocytes (TILs) and worse prognosis. Accordingly, downregulation of PDL1 inhibits pancreatic tumor cell proliferation. Furthermore, increased expression of inhibitory molecules on inactivated T cells has been suggested as another way to induce pancreatic cancer immunosuppression. Thus, pancreatic tumors show a high expression of CD40, a cell membrane receptor of the tumor necrosis factor family that modulates immune response, and this overexpression is associated to higher TNM Classification of Malignant Tumours (TNM) staging and metastasis.

Another reason to explain the PDA immunosuppressive phenotype might be its mutational signature. Indeed, recent cancer mutational analyses have demonstrated high variability among tumors, indicating that those tumors with increased mutation rate, like melanoma or lung, are highly immunogenic while those with low mutation rate, as PDA, are poorly antigenic. Interestingly, very recent data have indicated that neoantigen quality, rather than quantity, may modulate immunogenicity of PDA. This study suggests that the immune response against neoantigens with unique qualities generated during pancreatic tumor evolution, such as neoantigens in mucin 16, can lead to decreased relapse and the best prognosis. Further studies to identify other PDA immunogenic hotspots could be encouraging for the development of neoantigen-targeted strategies for treating checkpoint blockade-resistant patients which, unfortunately, are the vast majority.

3. Immune Checkpoints in PDA

Immune checkpoints refer to several co-stimulatory and inhibitory signals in immune cells that, in physiological conditions, prevent autoimmunity and constrict tissue damage during infections. However, these pathways can be hijacked by tumor cells to achieve immune evasion. Among the many different immune checkpoints that regulate T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD1) are the most well characterized and studied for cancer immunotherapy.

CTLA4 is expressed by activated T cells and Tregs and binds to its ligands B7-1/CD80 and B7-2/CD86 on the surface of antigen-presenting cells, which leads to downregulation of T helper cells and enhancement of Treg-mediated immune suppression. Interestingly, a blockade of CTLA4 in preclinical murine cancer models restores effector T-cells and decreases Tregs in melanoma and colorectal cancer, demonstrating the important role of this molecule in tumor immune evasion. As PDA is characterized for its highly immunosuppressive stroma rich in Tregs, a CTLA4 immune checkpoint emerges as a promising target also for PDA treatment. Indeed, recent data by Bengsch et al. using PDA mouse models have demonstrated that blocking CTLA4 in Tregs induces CD4+ T-cell tumor infiltration, suggesting an important role for pancreatic cancer immunotherapy. However, PDA patients enrolled in clinical trials with α-CTLA4 immunotherapy failed to respond to the treatment. Similar results were obtained in a genetically-engineered PDA murine model (KPC model), in which treatment with α-CTLA4 monoclonal antibodies (mAbs) showed no effects on tumor growth or survival. Nonetheless, T-cell stimulation with agonistic α-CD40 mAbs plus gemcitabine and nab-paclitaxel induced tumor regression and increased survival, suggesting that CD40-mediated induction of the T-cell response can overcome PDA resistance to α-CTLA4 immunotherapy (see below). In contrast, other studies using a PDA model after Panc02 subcutaneous injection showed tumor rejection in 50% of mice after α-CTLA4 treatment. These discrepancies in α-CTLA4 therapy efficacy can be a consequence of the origin of Panc02 cells, which are derived from a mouse tumor generated by carcinogen induction and, therefore, are probably hypermutated and display higher antigenicity than KPC tumors (and most human PDAs, see Section 2 (PDA Tumor Heterogeneity and Immune Responses).

Regarding the PD1/PDL1 immune checkpoint, PDL1 overexpression has been reported in PDA tumors, both in tumor cells and in the scarce immune infiltrates, and increased PDL1 expression is associated with poor survival. Controversial data regarding the correlation of PDL1 expression and presence of infiltrating CD8+ T cells have been reported. PD1 has been found to be expressed in about half of pancreatic tumor cytotoxic infiltrates. Overexpression of PDL1 is also found in the KPC mouse model of PDA, for which moderate staining was observed in around 40% of tumor cells as well as in stromal dendritic cells (DCs) and macrophages, which express higher PDL1 levels than their counterparts in the spleen. Moreover, tumor-infiltrating T-lymphocytes, including Tregs and few CD4+ and CD8+ T cells, also express PD1 at higher levels than that of the spleen populations. These results point to a role of the PD1/PDL1 immune checkpoint in PDA immune evasion. Similar to α-CTLA4 therapy, Pan02 tumors provide objective responses to α-PD1 or α-PDL1 therapies. However, KPC tumors are refractory to α-PD1 or α-PDL1 mAbs, either alone or in combination with α-CTLA4 therapy; this resistance could be reverted, however, by combined treatment with α-CD40 and chemotherapy. Importantly, Winograd et al. demonstrated that this combined regimen not only induces tumor rejection in a CD8+ T-cell-dependent manner, but also increases the capability of mice to reject subsequent tumor insults, suggesting that an anti-tumor immune memory with high therapeutic potential is generated. Indeed ongoing clinical trials in patients with α-CD40 are giving promising results (see below).

4. Role of Galectins in Immune Evasion in PDA

Among the different mechanisms involved in immune evasion, galectins—a family of proteins with high affinity for β-galactoside residues—have recently emerged as one of the key players in the regulation of lymphoid and myeloid cells in cancer. This family comprises 15 members, which share a consensus carbohydrate recognition domain (CRD) responsible for their glycan binding. Some galectins contain only one CRD and are active as monomers (galectin [Gal]-5, -7, and -10) or dimers (Gal-1, -2, -11, -13, -14, and -15), while Gal-4, -6, -8, -9, and -12 contain two CRD linked by a short peptide. Gal-3 is the only member that contains one CRD and a non-lectin domain, which allows its oligomerization. Although galectins can act both via sugar-dependent and sugar-independent interactions, most of their biological functions are via interactions with glycosylated proteins on the cell surface or in the extracellular matrix, playing key roles in cell-cell adhesion, migration and signaling. Galectins can be localized in different cell compartments and also secreted extracellularly through a non-classical secretory pathway.

Importantly, altered expression of different members of the galectin family has been reported in several cancer types. In particular, Gal-1 overexpression is frequently associated with poor prognosis of many tumors, while Gal-3 and Gal-9 expression are tumor type–dependent. Overexpression of galectins in cancer induce pro-tumoral functions like proliferation, epithelial to mesenchymal transition, angiogenesis and, remarkably, tumor immune evasion.

The role of galectins in the regulation of immune system has been widely studied. Gal-1 can recognize a variety of glycoproteins on the T-cell surface, inhibiting transendothelial T-cell migration, T-cell activation and, importantly, promoting apoptosis of activated Th1 and Th17 CD8+ T cells, thereby tilting the immune balance towards a Th2 profile. Additionally, Gal-1 can induce Treg and DC differentiation, impair NK cell recruitment to the tumor, induce M2 macrophage polarization and promote expansion of MDSCs and γδ-T cells. Altogether, these modulatory functions on different immune cell populations lead to a key role for Gal-1 in immune evasion, both in physiology during self-recognition and in pathology during cancer progression. Gal-1’s contribution to tumor immunosuppression has also been reported in PDA. Pancreatic stellate cells (PSC) are responsible for Gal-1 secretion and overexpression in the tumor microenvironment. In this context, extracellular Gal-1 secreted by PSC reduces viability of both CD4+ and CD8+ infiltrating activated T-cells. Moreover, a high level of Gal-1 favors a significant anti-tumor Th2 cytokine secretion and a drastically decrease of Th1 cytokine production. Importantly, Gal-1 is highly expressed in the stroma of human and murine pancreatic tumors, where it drives tumor progression through stroma activation, induced angiogenesis tumor cell proliferation and acinar-to-ductal metaplasia. Of note, when genetically inhibiting Gal-1, tumors show a significantly enhanced number of T-cell infiltrates and neutrophils, suggesting that galectin-1 may be key in driving immune evasion in PDA.

Gal-3 regulates immune system responses that act as a chemoattractant for monocytes and macrophages, impairing NK anti-tumor function. It also controls expansion of DCs and is able to modulate T-cell responses through apoptosis, T-cell receptor downregulation and crosslinking, consequently inhibiting T-cell activation. Gal-3 also promotes reduced immune response by decreasing IL-5 production and blocking B lymphocyte differentiation. Interestingly, in PDA, treating tumor-infiltrating CD8+ T-cells with α-Gal-3 mAb boosts their activation by increased IFNγ secretion. Upon ex vivo restimulation, the polysaccharide GCS-100, which is in clinical development, can detach Gal-3 from TILs. This favors activation of both CD8+ and CD4+ T cells and secretion of anti-tumor cytokines. Importantly, in vaccinated tumor-bearing mice, GCS-100 injections result in tumor regression. Of note, Gal-3 binding to LAG-3 induces CD8+ T cell suppression in vitro and Gal-3 KO mice show increased T effector functions upon GM-CSF vaccine administration. Indeed, phase I clinical trials (with still inconclusive results) have already been designed with Gal-3 inhibitors in combination with peptide vaccines, as well as with the immune checkpoint inhibitors ipilimumab (α-CTLA4) and pembrolizumab (α-PD1), in metastatic melanoma. Importantly, Gal-3 has already been added to the list of “new generation” checkpoints in immunotherapy.

Finally, Gal-9 also has crucial roles in controlling immune regulatory circuits, both in immune cell homeostasis and during cancer immune surveillance. Gal-9 can induce Treg cell differentiation and promote expansion of immunosuppressive MDSCs. Importantly, it specifically triggers apoptosis by interacting with TIM-3 in Th1 and CD8+ T cells, which has also placed Gal-9 in the “new generation” checkpoint list. Interestingly, Gal-9 has the ability to modulate immune responses in PDA. Gal-9 is a ligand for dectin-1, which is an innate immune receptor highly expressed in macrophages in PDA. The dectin-1/Gal-9 axis plays a key role in promoting differentiation of TAMs to a M2-like phenotype. Importantly, Gal-9 inhibition restores intratumoral T-cell infiltrates in PDA, but this function is impaired in the context of a dectin-1 deletion, suggesting that the dectin-1/Gal-9 interaction is key in reprogramming CD4+ and CD8+ T-cells for regulating tumor progression; thus, highlighting these players as targets in immunotherapy.

5. Other Molecular Mechanisms of Immune Escape in PDA

Preclinical evaluation of checkpoint inhibitors in PDA therapy has been considered; however, as PDA is a non-immunogenic tumor, monotherapy blocking of the PD1/PDL1 axis or CTLA4 have not been successful. Nevertheless, strategies stimulating the immune system in parallel with other treatments have shed some light on the field and present promising outcomes.

An α-CD40 antibody plus chemotherapy alters the phenotype of TILs, and, in combination with α-PD1 or α-CTLA4, or both, leads to regression of established tumors due to reduced number of Tregs and enhanced CD8:Treg ratio. Interestingly, Feig et al. reported that depletion of FAP+ cells in the tumor hampered tumor growth, due to increased infiltrating CD4+ and CD8+ T-cells, and synergized with checkpoint monotherapies. C-X-C motif chemokine ligand 12 (CXCL12) was found to be the chemokine responsible for recruiting effector T cells, and targeting its receptor (CXCR4) resulted in reduced pancreatic tumor growth in a T-cell-dependent manner. In combination with α-PDL1, the number of proliferating cancer cells in tumors are greatly reduced. Additionally, in a more recent report, CXCR2 inhibitors (which increase the amount of infiltrating CD3+ T-cells in KPC mice) were administered in a priming phase to enhance pancreatic T-cell infiltration, and animals were subsequently treated with either a combination of CXCR2 inhibitors and α-PD1 or directly with α-PD1 as a control. Immune checkpoint blockade proved to be efficient when targeting CXCR2 in parallel, significantly increasing animal survival by reducing the proliferation tumor rates as well as enhancing the proportion of both CD4+ and CD8+ T cells while diminishing Tregs. IL-6 blockade in combination with α-PDL1 also increased T-cell infiltration and synergistic outcomes in immunocompetent mouse models. Ruxolitinib (a JAK-Stat inhibitor), which inhibits systemic inflammation in the stroma of pancreatic cancer, also enhances cytotoxic T lymphocyte infiltration and boosts α-PD1 therapy in an orthotopic mouse model of PDA.

Multiple additional different designs have been proposed in preclinical studies to target the PDA immunosuppressive microenvironment and to increase immunotherapy efficiency, such as combinations with chemotherapy, radiation, therapeutic vaccines, or even several of these together. For instance, addition of α-PDL1 to high radiotherapy doses improved responses in KPC and Pan02 allografts, by shifting the balance towards increased CD8+ T cells at the expense of reducing CD11b+Gr1+ myeloid infiltrations. The combination of checkpoint inhibitors with therapeutic vaccines to prime the microenvironment with effector T cells before repressing the inhibitory signals has also shown impressive results. For example, GVAX together with α-PD1 therapy improves survival of tumor-bearing mice. More sophisticated mechanisms have also provided alternatives to increase immunotherapy efficiency, such as targeting the MLL1-H3K4me3 epigenetic axis or using antiangiogenic therapy to form intratumoral HEVs (high endothelial venules) to facilitate CTL tumor infiltration.

6. PDA and Immunotherapy

Pancreatic cancer clearly remains in dire needs of efficient treatment options. Considering that the current chemotherapy regimens have only led to extremely low levels of improvement in survival rates, and in light of the data showing that the immunosuppressive microenvironment is a feasible source of resistance, immunotherapy in clinical trials has raised high expectations. However, results from the initial studies with checkpoint inhibitors have not met expectations, and more sophisticated combinations are now being contemplated.

The first pathways to be tested in clinical trials concerned checkpoint inhibitions (Figure 1). α-CTLA4 ipilimumab was assessed in a phase II clinical trial in patients with advanced disease. RECIST (response evaluation criteria in solid tumors) reported an overall lack of response, although the condition of one patient (of 27) did improve due to the treatment. Several clinical trials with ipilimumab have been organized, which combine it with chemotherapy and/or stimulators of the immune response, such as GVAX; these have achieved mild improvements in overall survival (OS) and one-year OS. Most of these combinatory clinical trials have not yet published their results. A phase I dose escalation of another α-CTLA4 (tremelimumab) has been also performed in patients with metastatic pancreatic cancer, opening the door to further advanced clinical trials to evaluate its safety and efficacy, alone or in combination with radiation and other immune checkpoint inhibitors. The first results on treating pancreatic cancer with α-PD1 pembrolizumab have just been published. The PembroPlus phase Ib study studied the safety of combinations of α-PD1 and different chemotherapy agents, although conclusions about efficiency require further data. A phase Ib/II study of gemcitabine, nab-paclitaxel and pembrolizumab in 17 metastatic PDA patients was recently presented without meeting its primary endpoint. Twenty clinical trials with pembrolizumab in pancreatic cancer are active at the moment. BMS-956559 α-PDL1 achieved good performance in a phase I study with different solid tumors, although no objective responses were observed in pancreatic cancer patients. Eleven clinical trials are running with α-PDL1 durvalumab in pancreatic cancer, in different combinations. Although CTLA4 and PD1/PDL1 are the most well-studied immune checkpoints, other molecules of this type, such as LAG-3, TIM-3, and A2AR, also function to shut down the immune response and are also being considered for immunotherapy in clinical trials.

Therapeutic cancer vaccines using cancer cell antigens mixed with agents that stimulate patient immune responses have shown impressive results in several tumors and are also in the spotlight in pancreatic cancer clinical trials (Figure 1). For instance, GVAX (a GM-CSF vaccine) presented favorable results in a phase I study and phase II studies in combination with cyclophosphamide (to reduce Tregs) or chemoradiation, uncovering an interesting prognostic factor through the correlation between induction of mesothelin-specific T-cell responses with improved overall survival. Additionally, a phase II clinical trial that used GVAX in combination with CRS-207 (a live-attenuated strain of a Listeria monocytogenes–encoded mesothelin), to enhance both the innate and adaptive immunity, showed improved overall survival. Positive results for the vaccine Algenpantucel-L have also been published in a phase II study in combination with gemcitabine or fluorouracil, leading to ongoing promising phase III clinical trials (IMPRESS and PILLAR trials). Clinical trials with peptide vaccines instead of whole-cell vaccines have also been organized. A phase I/II trial with K-Ras peptides in combination with GM-CSF was performed, with partial positive responses. Further evidence for the potential of using a Ras vaccine in pancreatic cancer was demonstrated by a subsequent trials, with encouraging results and impressive 10-year follow-ups. Interestingly, the GI-4000 vaccine (which triggers an immune response against mutated Ras) has also drawn clinician’s attention. The telomerase peptide vaccine (GV1001) showed successful results in a phase I/II trial, although phase III clinical trials with chemotherapy regimens have not been able to show a survival advantage. Although different results have been achieved depending on combinations, other peptide-based vaccines have also led to pancreatic cancer patients inducing an antibody response but without achieving impressive results; these include the MUC1 vaccines, anti-VEGFR vaccines, survivin, anti-gastrin, anti-heat shock protein vaccine, and anti-WT-1. Dendritic cell vaccines are also under investigation in pancreatic cancer clinical trials, highlighting carcinoembryonic antigen (CEA)-loaded DCs, mutated p53 and K-Ras loaded DCs, MUC1, and WT-1 pulsed DCS. Interestingly, very recently publications have shown that therapy with DCs together with CIK (cytokine-induced killer cells) and chemotherapy associates with increased immune responses, resulting in favorable progression free survival and OS.

Another strategy that is revolutionizing cancer immunotherapy is adoptive T-cell therapy, in which autologous or allogenic tumor-specific cytotoxic T cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumor cells. The most universal approach is to using T cells that are genetically modified to express chimeric antigen receptors (CARs) specific tumor-associated antigens (such as CEA, EGFR, Her2, MUC1, mesothelin, CD24, and PSCA). This strategy has performed relatively well in pancreatic cancer preclinical studies. However, taking the plunge to the clinic has not proven as successful, probably due to the tumor immunosuppressive microenvironment, and neoadjuvant chemoradiation and combinations with costimulators are now being explored (Figure 1). Interestingly, strategies have been designed to enhance CAR T-cell therapy efficiency, such as reducing tumor bulk before adoptive cell therapy, optimizing the Th2-to-Th1 ratio of infused CAR T-cells, pre-conditioning to deplete Tregs (by inhibiting CTLA4, CD-25 targeting, TNFα agonism or combining with rosiglitazone), increasing CD8+ TILS (with metformin or by inhibiting TGF-β), increasing macrophage activation (by targeting CSF1, CCR2 or Bruton tyrosine kinase (BTK)) and even co-expressing albumin on the surface of CAR T-cells (to enhance accumulation in the tumor).

Considering that the strong immunosuppressive barrier is a handicap in pancreatic cancer therapy, approaches with immune-modulating agents are also being considered in clinical trials (Figure 1). A CD40 agonist antibody was combined with gemcitabine for treating 22 advanced PDA patients; this achieved promising results and opens the door to a couple more clinical trials with CD40 agonist and chemotherapy, with results yet to be published. In a similar context, inhibition of CCR2 to target TAMs and monocytes in combination with folfirinox led to either stabilization of disease or partial response in all of the patients who could be evaluated according to RECIST.

An interesting meta-analysis gathering all clinical trials with immunotherapies in pancreatic cancer found out that this strategy indeed significantly increases the 3-, 6-, 12-month and 3-year OS of patients. Importantly, immunotherapy significantly increases the immune response of patients with PDA and reduced CA19-9 levels.

In conclusion, a large effort to fit immunotherapy into pancreatic cancer therapies is being made by companies and clinicians, but it is still far from being the panacea. The strong immunosuppressive PDA microenvironment becomes a double-edged sword: on one hand, it makes immunotherapy a reasonable option as a therapy, but on the other, it is, per se, a stumbling block rather than a stepping stone that hinders very much its own efficiency. More sophisticated combinations and personalized patient stratification will be necessary to achieve favorable outcomes and implement this as practical therapy in the clinics.

7. Concluding Remarks

Pancreatic cancer has a complex molecular landscape that handicaps both research advances and therapy efficiency. The strong immunosuppressive microenvironment in PDA, which mainly consists of Tregs, macrophages, and MDSCs, blocks T effector cells, leading to immune evasion and rapid tumor progression. Indeed, checkpoint monotherapies have failed in clinical trials due to this strong immunological barrier. The main actor driving this process to bypass immune surveillance is a tangled combination of chemokines and receptor-ligand signaling pathways, both in the tumor and the stroma, and understanding this is critical to target the key regulators and allow immunotherapy to be efficient. In this direction, basic research and preclinical trials with immunocompetent mice have shed some light on the exact molecular mechanisms involved but are also raising concerns about the complexity of the issue and the feasibility of deriving a combination that is suitable for a high percentage of patients. Indeed, of the roughly a hundred clinical trials with immunotherapy in pancreatic cancer that have been designed, none have achieved impressive results, although clearly some of the patients have had with objective responses and may benefit from the therapies boosting their immune systems. In this regard, new ultrasequencing data from cancer international consortiums have allowed human pancreatic tumors to be classified according to their molecular signature; this has unveiled a new immunogenic subtype that might be more sensitive to immunotherapy. Once again, it seems that we are underestimating the heterogeneity of cancer disease, and that although economic issues cannot be undervalued, the real solution will need to approach the issue through personalized medicine.

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    Gabrilovich D.I., Chen H.L., Girgis K.R., Cunningham H.T., Meny G.M., Nadaf S., Kavanaugh D., Carbone D.P. Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells. Nat. Med. 1996;2:1096-1103.

    Not in our library10.1038/nm1096-1096

  19. 19.

    Driessens G., Kline J., Gajewski T.F. Costimulatory and coinhibitory receptors in anti-tumor immunity. Immunol. Rev. 2009;229:126-144.

    Not in our library10.1111/j.1600-065x.2009.00771.x

  20. 20.

    Topalian S.L., Drake C.G., Pardoll D.M. Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 2012;24:207-212.

    Not in our library10.1016/j.coi.2011.12.009

  21. 21.

    French L.E., Tschopp J. Defective death receptor signaling as a cause of tumor immune escape. Semin. Cancer Biol. 2002;12:51-55.

    Not in our library10.1006/scbi.2001.0405

  22. 22.

    Berraondo P., Minute L., Ajona D., Corrales L., Melero I., Pio R. Innate immune mediators in cancer: Between defense and resistance. Immunol. Rev. 2016;274:290-306.

    Not in our library10.1111/imr.12464

  23. 23.

    Jones S., Zhang X., Parsons D.W., Lin J.C., Leary R.J., Angenendt P., Mankoo P., Carter H., Kamiyama H., Jimeno A., et al. Core signaling pathways in human pancreatic cancers revealed by global genomic analyses. Science. 2008;321:1801-1806.

    Not in our library10.1126/science.1164368

  24. 24.

    Biankin A.V., Waddell N., Kassahn K.S., Gingras M.-C., Muthuswamy L.B., Johns A.L., Miller D.K., Wilson P.J., Patch A.-M., Wu J., et al. Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature. 2012;491:399-405.

    Not in our library10.1038/nature11547

  25. 25.

    Waddell N., Pajic M., Patch A.-M., Chang D.K., Kassahn K.S., Bailey P., Johns A.L., Miller D., Nones K., Quek K., et al. Whole genomes redefine the mutational landscape of pancreatic cancer. Nature. 2015;518:495-501.

    Not in our library10.1038/nature14169

  26. 26.
    Whole-exome sequencing of pancreatic cancer defines genetic diversity and therapeutic targets · 2015
    No notice
  27. 27.

    Bailey P., Chang D.K., Nones K., Johns A.L., Patch A.-M., Gingras M.-C., Miller D.K., Christ A.N., Bruxner T.J.C., Quinn M.C., et al. Genomic analyses identify molecular subtypes of pancreatic cancer. Nature. 2016;531:47-52.

    Not in our library10.1038/nature16965

  28. 28.

    Raphael B.J., Hruban R.H., Aguirre A.J., Moffitt R.A., Yeh J.J., Stewart C., Robertson A.G., Cherniack A.D., Gupta M., Getz G., et al. Integrated Genomic Characterization of Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2017;32:185-203.e13.

    Not in our library10.1016/j.ccell.2017.07.007

  29. 29.

    Liyanage U.K., Moore T.T., Joo H.-G., Tanaka Y., Herrmann V., Doherty G., Drebin J.A., Strasberg S.M., Eberlein T.J., Goedegebuure P.S., et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 2002;169:2756-2761.

    Not in our library10.4049/jimmunol.169.5.2756

  30. 30.

    Zhao F., Obermann S., von Wasielewski R., Haile L., Manns M.P., Korangy F., Greten T.F. Increase in frequency of myeloid-derived suppressor cells in mice with spontaneous pancreatic carcinoma. Immunology. 2009;128:141-149.

    Not in our library10.1111/j.1365-2567.2009.03105.x

  31. 31.

    Amedei A., Niccolai E., Benagiano M., Della B.C., Cianchi F., Bechi P., Taddei A., Bencini L., Farsi M., Cappello P., et al. Ex vivo analysis of pancreatic cancer-infiltrating T lymphocytes reveals that ENO-specific Tregs accumulate in tumor tissue and inhibit Th1/Th17 effector cell functions. Cancer Immunol. Immunother. 2013;62:1249-1260.

    Not in our library10.1007/s00262-013-1429-3

  32. 32.

    Ino Y., Yamazaki-Itoh R., Shimada K., Iwasaki M., Kosuge T., Kanai Y., Hiraoka N. Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer. Br. J. Cancer. 2013;108:914-923.

    Not in our library10.1038/bjc.2013.32

  33. 33.

    Clark C.E., Hingorani S.R., Mick R., Combs C., Tuveson D.A., Vonderheide R.H. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 2007.

    Not in our library10.1158/0008-5472.can-07-0175

  34. 34.

    Tan M.C.B., Goedegebuure P.S., Belt B.A., Flaherty B., Sankpal N., Gillanders W.E., Eberlein T.J.H., Chyi-Song L., David C. Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer. J. Immunol. 2009;182:1746-1755.

    Not in our library10.4049/jimmunol.182.3.1746

  35. 35.

    Mitchem J.B., Brennan D.J., Knolhoff B.L., Belt B.A., Zhu Y., Sanford D.E., Belaygorod L., Carpenter D., Collins L., Piwnica-Worms D., et al. Targeting tumor-infiltrating macrophages decreases tumor-initiating cells, relieves immunosuppression, and improves chemotherapeutic responses. Cancer Res. 2013;73:1128-1141.

    Not in our library10.1158/0008-5472.can-12-2731

  36. 36.

    Chen L., Flies D.B. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat. Rev. Immunol. 2013;13:227-242.

    Not in our library10.1038/nri3405

  37. 37.

    Saqib R., Noman A., Julio C.C., Mokenge P.M., Domenico C., Gregory M.S., Helm J., Kim R.D. Expression of programmed death ligand 1 (PD-L1) in malignant and nonmalignant pancreatic tissue. J. Clin. Oncol. 2013;31:215.

    Not in our library

  38. 38.

    Nomi T., Sho M., Akahori T., Hamada K., Kubo A., Kanehiro H., Nakamura S., Enomoto K., Yagita H., Azuma M., et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin. Cancer Res. 2007;13:2151-2157.

    Not in our library10.1158/1078-0432.ccr-06-2746

  39. 39.

    Geng L., Huang D., Liu J., Qian Y., Deng J., Li D., Hu Z., Zhang J., Jiang G., Zheng S., et al. B7-H1 up-regulated expression in human pancreatic carcinoma tissue associates with tumor progression. J. Cancer Res. Clin. Oncol. 2008;134:1021-1027.

    Not in our library10.1007/s00432-008-0364-8

  40. 40.

    Song X., Liu J., Lu Y., Jin H., Huang D. Overexpression of B7-H1 correlates with malignant cell proliferation in pancreatic cancer. Oncol. Rep. 2014;31:1191-1198.

    Not in our library10.3892/or.2013.2955

  41. 41.

    Li D., Zhao H., Fei M., Wu Y., Wang L., Zhu X., Li D. Expression of the co-signaling molecules CD40-CD40L and their growth inhibitory effect on pancreatic cancer in vitro. Oncol. Rep. 2012;28:262-268.

    Not in our library10.3892/or.2012.1790

  42. 42.

    Lawrence M.S., Stojanov P., Polak P., Kryukov G.V., Cibulskis K., Sivachenko A., Carter S.L., Stewart C., Mermel C.H., Roberts S.A., et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214-218.

    Not in our library10.1038/nature12213

  43. 43.

    Alexandrov L.B., Nik-Zainal S., Wedge D.C., Aparicio S.A.J.R., Behjati S., Biankin A.V., Bignell G.R., Bolli N., Borg A., Børresen-Dale A.-L., et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415-421.

    Not in our library10.1038/nature12477

  44. 44.

    Beatty G.L., Gladney W.L. Immune escape mechanisms as a guide for cancer immunotherapy. Clin. Cancer Res. 2015.

    Not in our library10.1158/1078-0432.ccr-14-1860

  45. 45.

    Balachandran V.P., Łuksza M., Zhao J.N., Makarov V., Moral J.A., Remark R., Herbst B., Askan G., Bhanot U., Senbabaoglu Y., et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature. 2017.

    Not in our library10.1038/nature24462

  46. 46.

    Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 2012;12:252-264.

    Not in our library10.1038/nrc3239

  47. 47.

    Melero I., Berman D.M., Aznar M.A., Korman A.J., Gracia J.L.P., Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. Rev. Cancer. 2015;15:457-472.

    Not in our library10.1038/nrc3973

  48. 48.

    Odorizzi P.M., Wherry E.J. Inhibitory receptors on lymphocytes: Insights from infections. J. Immunol. 2012;188:2957-2965.

    Not in our library10.4049/jimmunol.1100038

  49. 49.

    Peggs K.S., Quezada S.A., Chambers C.A., Korman A.J., Allison J.P. Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 2009;206:1717-1725.

    Not in our library10.1084/jem.20082492

  50. 50.

    Simpson T.R., Li F., Montalvo-Ortiz W., Sepulveda M.A., Bergerhoff K., Arce F., Roddie C., Henry J.Y., Yagita H., Wolchok J.D., et al. Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma. J. Exp. Med. 2013;210:1695-1710.

    Not in our library10.1084/jem.20130579

  51. 51.

    Selby M.J., Engelhardt J.J., Quigley M., Henning K.A., Chen T., Srinivasan M., Korman A.J. Anti-CTLA-4 Antibodies of IgG2a Isotype Enhance Antitumor Activity through Reduction of Intratumoral Regulatory T Cells. Cancer Immunol. Res. 2013;1:32-42.

    Not in our library10.1158/2326-6066.cir-13-0013

  52. 52.

    Bengsch F., Knoblock D.M., Liu A., McAllister F., Beatty G.L. CTLA-4/CD80 pathway regulates T cell infiltration into pancreatic cancer. Cancer Immunol. Immunother. 2017;66:1609-1617.

    Not in our library10.1007/s00262-017-2053-4

  53. 53.

    Brahmer J.R., Tykodi S.S., Chow L.Q.M., Hwu W.-J., Topalian S.L., Hwu P., Drake C.G., Camacho L.H., Kauh J., Odunsi K., et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 2012;366:2455-2465.

    Not in our library10.1056/nejmoa1200694

  54. 54.

    Royal R.E., Levy C., Turner K., Mathur A., Hughes M., Kammula U.S., Sherry R.M., Topalian S.L., Yang J.C., Lowy I., et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J. Immunother. 2010;33:828-833.

    Not in our library10.1097/cji.0b013e3181eec14c

  55. 55.

    Le D.T., Lutz E., Uram J.N., Sugar E.A., Onners B., Solt S., Zheng L., Diaz L.A., Donehower R.C., Jaffee E.M., et al. Evaluation of ipilimumab in combination with allogeneic pancreatic tumor cells transfected with a GM-CSF gene in previously treated pancreatic cancer. J. Immunother. 2013;36:382-389.

    Not in our library10.1097/cji.0b013e31829fb7a2

  56. 56.

    Winograd R., Byrne K.T., Evans R.A., Odorizzi P.M., Meyer A.R.L., Bajor D.L., Clendenin C., Stanger B.Z., Furth E.E., Wherry E.J., et al. Induction of T-cell Immunity Overcomes Complete Resistance to PD-1 and CTLA-4 Blockade and Improves Survival in Pancreatic Carcinoma. Cancer Immunol. Res. 2015.

    Not in our library10.1158/2326-6066.cir-14-0215

  57. 57.

    Sandin L.C., Eriksson F., Ellmark P., Loskog A.S., Tötterman T.H., Mangsbo S.M. Local CTLA4 blockade effectively restrains experimental pancreatic adenocarcinoma growth in vivo. Oncoimmunology. 2014;3:e27614.

    Not in our library10.4161/onci.27614

  58. 58.

    Corbett T.H., Roberts B.J., Leopold W.R., Peckham J.C., Wilkoff L.J., Griswold D.P., Schabel F.M. Induction and chemotherapeutic response of two transplantable ductal adenocarcinomas of the pancreas in C57BL/6 mice. Cancer Res. 1984;44:717-726.

    Not in our library

  59. 59.

    Lu C., Paschall A.V., Shi H., Savage N., Waller J.L., Sabbatini M.E., Oberlies N.H., Pearce C., Liu K. The MLL1-H3K4me3 Axis-Mediated PD-L1 Expression and Pancreatic Cancer Immune Evasion. J. Natl. Cancer Inst. 2017;109:djw283.

    Not in our library10.1093/jnci/djw283

  60. 60.

    Okudaira K., Hokari R., Tsuzuki Y., Okada Y., Komoto S., Watanabe C., Kurihara C., Kawaguchi A., Nagao S., Azuma M., et al. Blockade of B7-H1 or B7-DC induces an anti-tumor effect in a mouse pancreatic cancer model. Int. J. Oncol. 2009;35:741-749.

    Not in our library10.3892/ijo_00000387

  61. 61.

    Beatty G.L., Torigian D.A., Chiorean E.G., Saboury B., Brothers A., Alavi A., Troxel A.B., Sun W., Teitelbaum U.R., Vonderheide R.H., et al. A Phase I Study of an Agonist CD40 Monoclonal Antibody (CP-870,893) in Combination with Gemcitabine in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Clin. Cancer Res. 2013;19:6286-6295.

    Not in our library10.1158/1078-0432.ccr-13-1320

  62. 62.

    Barondes S.H., Castronovo V., Cooper D.N., Cummings R.D., Drickamer K., Feizi T., Gitt M.A., Hirabayashi J., Hughes C., Kasai K., et al. Galectins: A family of animal beta-galactoside-binding lectins. Cell. 1994;76:597-598.

    Not in our library10.1016/0092-8674(94)90498-7

  63. 63.

    Leffler H., Carlsson S., Hedlund M., Qian Y., Poirier F. Introduction to galectins. Glycoconj. J. 2002;19:433-440.

    Not in our library10.1023/b:glyc.0000014072.34840.04

  64. 64.

    Cerliani J.P., Blidner A.G., Toscano M.A., Croci D.O., Rabinovich G.A. Translating the “Sugar Code” into Immune and Vascular Signaling Programs. Trends Biochem. Sci. 2017;42:255-273.

    Not in our library10.1016/j.tibs.2016.11.003

  65. 65.

    Cooper D.N.W. Galectinomics: Finding themes in complexity. Biochim. Biophys. Acta. 2002;1572:209-231.

    Not in our library10.1016/s0304-4165(02)00310-0

  66. 66.

    Liu F.T., Rabinovich G.A. Galectins as modulators of tumour progression. Nat. Rev. Cancer. 2005;5:29-41.

    Not in our library10.1038/nrc1527

  67. 67.

    Hughes R.C. Secretion of the galectin family of mammalian carbohydrate-binding proteins. Biochim. Biophys. Acta. 1999;1473:172-185.

    Not in our library10.1016/s0304-4165(99)00177-4

  68. 68.

    Demydenko D., Berest I. Expression of galectin-1 in malignant tumors. Exp. Oncol. 2009;31:74-79.

    Not in our library

  69. 69.

    Croci D.O., Salatino M., Rubinstein N., Cerliani J.P., Cavallin L.E., Leung H.J., Ouyang J., Ilarregui J.M., Toscano M.A., Domaica C.I., et al. Disrupting galectin-1 interactions with n-glycans suppresses hypoxia-driven angiogenesis and tumorigenesis in kaposi’s sarcoma. J. Exp. Med. 2012;209:1985-2000.

    Not in our library10.1084/jem.20111665

  70. 70.

    Croci D.O., Cerliani J.P., Dalotto-Moreno T., Méndez-Huergo S.P., Mascanfroni I.D., Dergan-Dylon S., Toscano M.A., Caramelo J.J., García-Vallejo J.J., Ouyang J., et al. Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors. Cell. 2014;156:744-758.

    Not in our library10.1016/j.cell.2014.01.043

  71. 71.

    Espelt M.V., Croci D.O., Bacigalupo M.L., Carabias P., Manzi M., Elola M.T., Munoz M.C., Dominici F.P., Wolfenstein-Todel C., Rabinovich G.A., et al. Novel roles of galectin-1 in hepatocellular carcinoma cell adhesion, polarization, and in vivo tumor growth. Hepatology. 2011;53:2097-2106.

    Not in our library10.1002/hep.24294

  72. 72.

    Thijssen V.L., Barkan B., Shoji H., Aries I.M., Mathieu V., Deltour L., Hackeng T.M., Kiss R., Kloog Y., Poirier F., et al. Tumor cells secrete galectin-1 to enhance endothelial cell activity. Cancer Res. 2010;70:6216-6224.

    Not in our library10.1158/0008-5472.can-09-4150

  73. 73.

    Bacigalupo M.L., Manzi M., Espelt M.V., Gentilini L.D., Compagno D., Laderach D.J., Wolfenstein-Todel C., Rabinovich G.A., Troncoso M.F. Galectin-1 Triggers Epithelial-Mesenchymal Transition in Human Hepatocellular Carcinoma Cells. J. Cell. Physiol. 2015;230:1298-1309.

    Not in our library10.1002/jcp.24865

  74. 74.

    Rabinovich G., Ramhorst R., Rubinstein N., Corigliano A., Daroqui M., Kier-Joffe E., Fainboim L. Induction of allogenic t-cell hyporesponsiveness by galectin-1-mediated apoptotic and non-apoptotic mechanisms. Cell Death Differ. 2002;9:661-670.

    Not in our library10.1038/sj.cdd.4401009

  75. 75.

    He J., Baum L.G. Presentation of galectin-1 by extracellular matrix triggers T cell death. J. Biol. Chem. 2004;279:4705-4712.

    Not in our library10.1074/jbc.m311183200

  76. 76.

    Méndez-Huergo S.P., Blidner A.G., Rabinovich G.A. Galectins: Emerging regulatory checkpoints linking tumor immunity and angiogenesis. Curr. Opin. Immunol. 2017;45:8-15.

    Not in our library10.1016/j.coi.2016.12.003

  77. 77.

    Rabinovich G.A., Conejo-García J.R. Shaping the Immune Landscape in Cancer by Galectin-Driven Regulatory Pathways. J. Mol. Biol. 2016;428:3266-3281.

    Not in our library10.1016/j.jmb.2016.03.021

  78. 78.

    Tang D., Yuan Z., Xue X., Lu Z., Zhang Y., Wang H., Chen M., An Y., Wei J., Zhu Y., et al. High expression of Galectin-1 in pancreatic stellate cells plays a role in the development and maintenance of an immunosuppressive microenvironment in pancreatic cancer. Int. J. Cancer. 2012;130:2337-2348.

    Not in our library10.1002/ijc.26290

  79. 79.

    Martínez-Bosch N., Fernández-Barrena M.G., Moreno M., Ortiz-Zapater E., Munné-Collado J., Iglesias M., André S., Gabius H.-J., Hwang R.F., Poirier F., et al. Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation. Cancer Res. 2014;74:3512-3524.

    Not in our library10.1158/0008-5472.can-13-3013

  80. 80.

    Martínez-Bosch N., Navarro P. Targeting Galectin-1 in pancreatic cancer: Immune surveillance on guard. Oncoimmunology. 2014;3:e952201.

    Not in our library10.4161/21624011.2014.952201

  81. 81.

    Martínez-Bosch N., Navarro P. Galectin-1 as a therapeutic target in pancreatic cancer: The tumor stroma in the spotlight. Cancer Cell Microenviron. 2014;1:1-6.

    Not in our library10.14800/ccm.296

  82. 82.

    Sano H., Hsu D.K., Yu L., Apgar J.R., Kuwabara I., Yamanaka T., Hirashima M., Liu F.-T., et al. Human galectin-3 is a novel chemoattractant for monocytes and macrophages. J. Immunol. 2000;165:2156-2164.

    Not in our library10.4049/jimmunol.165.4.2156

  83. 83.

    Demetriou M., Granovsky M., Quaggin S., Dennis J.W. Negative regulation of T-cell activation and autoimmunity by Mgat5 N-glycosylation. Nature. 2001;409:733-739.

    Not in our library10.1038/35055582

  84. 84.

    Acosta-Rodríguez E.V., Montes C.L., Motrán C.C., Zuniga E.I., Liu F.-T., Rabinovich G.A., Gruppi A., et al. Galectin-3 mediates IL-4-induced survival and differentiation of B cells: Functional cross-talk and implications during Trypanosoma cruzi infection. J. Immunol. 2004;172:493-502.

    Not in our library10.4049/jimmunol.172.1.493

  85. 85.

    Demotte N., Wieërs G., Van Der Smissen P., Moser M., Schmidt C., Thielemans K., Squifflet J.-L., Weynand B., Carrasco J., Lurquin C., et al. A Galectin-3 Ligand Corrects the Impaired Function of Human CD4 and CD8 Tumor-Infiltrating Lymphocytes and Favors Tumor Rejection in Mice. Cancer Res. 2010;70:7476-7488.

    Not in our library10.1158/0008-5472.can-10-0761

  86. 86.

    Kouo T., Huang L., Pucsek A.B., Cao M., Solt S., Armstrong T., Jaffee E. Galectin-3 Shapes Antitumor Immune Responses by Suppressing CD8+ T Cells via LAG-3 and Inhibiting Expansion of Plasmacytoid Dendritic Cells. Cancer Immunol. Res. 2015;3:412-423.

    Not in our library10.1158/2326-6066.cir-14-0150

  87. 87.

    Zhu C., Anderson A.C., Schubart A., Xiong H., Imitola J., Khoury S.J., Zheng X.X., Strom T.B., Kuchroo V.K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat. Immunol. 2005;6:1245-1252.

    Not in our library10.1038/ni1271

  88. 88.

    Topalian S.L., Drake C.G., Pardoll D.M. Immune checkpoint blockade: A common denominator approach to cancer therapy. Cancer Cell. 2015;27:450-461.

    Not in our library10.1016/j.ccell.2015.03.001

  89. 89.

    Daley D., Mani V.R., Mohan N., Akkad N., Ochi A., Heindel D.W., Lee K.B., Zambirinis C.P., Pandian G.S.B., Savadkar S., et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 2017.

    Not in our library10.1038/nm.4314

  90. 90.

    Feig C., Gopinathan A., Neesse A., Chan D.S., Cook N., Tuveson D.A. The pancreas cancer microenvironment. Clin. Cancer Res. 2013;18:4266-4276.

    Not in our library10.1158/1078-0432.ccr-11-3114

  91. 91.

    Luheshi N.M., Coates-Ulrichsen J., Harper J., Mullins S., Sulikowski M.G., Martin P., Brown L., Lewis A., Davies G., Morrow M., et al. Transformation of the tumour microenvironment by a CD40 agonist antibody correlates with improved responses to PD-L1 blockade in a mouse orthotopic pancreatic tumour model. Oncotarget. 2016;7:18508-18520.

    Not in our library10.18632/oncotarget.7610

  92. 92.

    Steele C.W., Karim S.A., Leach J.D., Bailey P., Upstill-Goddard R., Rishi L., Foth M., Bryson S., McDaid K., Wilson Z., et al. CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma. Cancer Cell. 2016;29:832-845.

    Not in our library10.1016/j.ccell.2016.04.014

  93. 93.

    Mace T.A., Shakya R., Pitarresi J.R., Swanson B., McQuinn C.W., Loftus S., Nordquist E., Cruz-Monserrate Z., Yu L., Young G., et al. IL-6 and PD-L1 antibody blockade combination therapy reduces tumour progression in murine models of pancreatic cancer. Gut. 2016.

    Not in our library10.1136/gutjnl-2016-311585

  94. 94.
    JAK-STAT-mediated chronic inflammation impairs cytotoxic T lymphocyte activation to decrease anti-PD-1 immunotherapy efficacy in pancreatic cancer · 2017
    Not checked
  95. 95.

    Zheng W., Skowron K.B., Namm J.P., Burnette B., Fernandez C., Arina A., Liang H., Spiotto M.T., Posner M.C., Fu Y.-X., et al. Combination of radiotherapy and vaccination overcomes checkpoint blockade resistance. Oncotarget. 2016;7:43039-43051.

    Not in our library10.18632/oncotarget.9915

  96. 96.
    PD‐L1 blockade enhances response of pancreatic ductal adenocarcinoma to radiotherapy · 2016
    No notice
  97. 97.

    Mahoney K.M., Rennert P.D., Freeman G.J. Combination cancer immunotherapy and new immunomodulatory targets. Nat. Rev. Drug. Discov. 2015;14:561-584.

    Not in our library10.1038/nrd4591

  98. 98.

    Soares K.C., Rucki A.A., Wu A.A., Olino K., Xiao Q., Chai Y., Wamwea A., Bigelow E., Lutz E., Liu L., et al. PD-1/PD-L1 blockade together with vaccine therapy facilitates effector T-cell infiltration into pancreatic tumors. J. Immunother. 2015;38:1-11.

    Not in our library10.1097/cji.0000000000000062

  99. 99.

    Allen E., Jabouille A., Rivera L.B., Lodewijckx I., Missiaen R., Steri V., Feyen K., Tawney J., Hanahan D., Michael I.P., et al. Combined antiangiogenic and anti–PD-L1 therapy stimulates tumor immunity through HEV formation. Sci. Transl. Med. 2017;9:eaak9679.

    Not in our library10.1126/scitranslmed.aak9679

  100. 100.

    Aglietta M., Barone C., Sawyer M., Moore M., Miller W., Bagalà C., Colombi F., Cagnazzo C., Gioeni L., Wang E., et al. A phase I dose escalation trial of tremelimumab (CP-675,206) in combination with gemcitabine in chemotherapy-naive patients with metastatic pancreatic cancer. Ann. Oncol. 2014;25:1750-1755.

    Not in our library10.1093/annonc/mdu205

  101. 101.

    Weiss G.J., Waypa J., Blaydorn L., Coats J., McGahey K., Sangal A., Niu J., Lynch C.A., Farley J.H., Khemka V., et al. A phase Ib study of pembrolizumab plus chemotherapy in patients with advanced cancer (PembroPlus). Br. J. Cancer. 2017;117:33-40.

    Not in our library10.1038/bjc.2017.145

  102. 102.

    Weiss G.J., Blaydorn L., Beck J., Bornemann-Kolatzki K., Urnovitz H., Schütz E., Khemka V. Phase Ib/II study of gemcitabine, nab-paclitaxel, and pembrolizumab in metastatic pancreatic adenocarcinoma. Invest. New Drugs. 2017.

    Not in our library10.1007/s10637-017-0525-1

  103. 103.

    Li X., Hu W., Zheng X., Zhang C., Du P., Zheng Z., Yang Y., Wu J., Ji M., Jiang J., et al. Emerging immune checkpoints for cancer therapy. Acta Oncol. 2015;54:1706-1713.

    Not in our library10.3109/0284186x.2015.1071918

  104. 104.

    Jaffee E.M., Hruban R.H., Biedrzycki B., Laheru D., Schepers K., Sauter P.R., Goemann M., Coleman J., Grochow L., Donehower R.C., et al. Novel allogeneic granulocyte-macrophage colony-stimulating factor-secreting tumor vaccine for pancreatic cancer: A phase I trial of safety and immune activation. J. Clin. Oncol. 2001;19:145-156.

    Not in our library10.1200/jco.2001.19.1.145

  105. 105.

    Laheru D., Lutz E., Burke J., Biedrzycki B., Solt S., Onners B., Tartakovsky I., Nemunaitis J., Le D., Sugar E., et al. Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: A pilot study of safety, feasibility, and immune activation. Clin. Cancer Res. 2008;14:1455-1463.

    Not in our library10.1158/1078-0432.ccr-07-0371

  106. 106.

    Lutz E., Yeo C.J., Lillemoe K.D., Biedrzycki B., Kobrin B., Herman J., Sugar E., Piantadosi S., Cameron J.L., Solt S., et al. A lethally irradiated allogeneic granulocyte-macrophage colony stimulating factor-secreting tumor vaccine for pancreatic adenocarcinoma: A Phase II trial of safety, efficacy, and immune activation. Ann. Surg. 2011;253:328-335.

    Not in our library10.1097/sla.0b013e3181fd271c

  107. 107.

    Le D.T., Wang-Gillam A., Picozzi V., Greten T.F., Crocenzi T., Springett G., Morse M., Zeh H., Cohen D., Fine R.L., et al. Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J. Clin. Oncol. 2015;33:1325-1333.

    Not in our library10.1200/jco.2014.57.4244

  108. 108.

    Hardacre J.M., Mulcahy M., Small W., Talamonti M., Obel J., Krishnamurthi S., Rocha-Lima C.S., Safran H., Lenz H.-J., Chiorean E.G., et al. Addition of Algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: A Phase 2 Study. J. Gastrointest. Surg. 2013;17:94-101.

    Not in our library10.1007/s11605-012-2064-6

  109. 109.

    Gjertsen M.K., Buanes T., Rosseland A.R., Bakka A., Gladhaug I., Søreide O., Eriksen J.A., Møller M., Baksaas I., Lothe R.A., et al. Intradermal ras peptide vaccination with granulocyte-macrophage colony-stimulating factor as adjuvant: Clinical and immunological responses in patients with pancreatic adenocarcinoma. Int. J. cancer. 2001;92:441-450.

    Not in our library10.1002/ijc.1205

  110. 110.

    Toubaji A., Achtar M., Provenzano M., Herrin V.E., Behrens R., Hamilton M., Bernstein S., Venzon D., Gause B., Marincola F., et al. Pilot study of mutant ras peptide-based vaccine as an adjuvant treatment in pancreatic and colorectal cancers. Cancer Immunol. Immunother. 2008;57:1413-1420.

    Not in our library10.1007/s00262-008-0477-6

  111. 111.

    Abou-Alfa G.K., Chapman P.B., Feilchenfeldt J., Brennan M.F., Capanu M., Gansukh B., Jacobs G., Levin A., Neville D., Kelsen D.P., et al. Targeting mutated K-ras in pancreatic adenocarcinoma using an adjuvant vaccine. Am. J. Clin. Oncol. 2011;34:321-325.

    Not in our library10.1097/coc.0b013e3181e84b1f

  112. 112.

    Wedén S., Klemp M., Gladhaug I.P., Møller M., Eriksen J.A., Gaudernack G., Buanes T. Long-term follow-up of patients with resected pancreatic cancer following vaccination against mutant K-ras. Int. J. Cancer. 2011;128:1120-1128.

    Not in our library10.1002/ijc.25449

  113. 113.

    Hartley M.L., Bade N.A., Prins P.A., Ampie L., Marshall J.L. Pancreatic cancer, treatment options, and GI-4000. Hum. Vaccin. Immunother. 2015;11:931-937.

    Not in our library10.1080/21645515.2015.1011017

  114. 114.
    Telomerase peptide vaccination of patients with non-resectable pancreatic cancer: a dose escalating phase I/II study · 2006
    No notice
  115. 115.

    Middleton G., Silcocks P., Cox T., Valle J., Wadsley J., Propper D., Coxon F., Ross P., Madhusudan S., Roques T., et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): An open-label, randomised, phase 3 trial. Lancet Oncol. 2014;15:829-840.

    Not in our library10.1016/s1470-2045(14)70236-0

  116. 116.

    Lepisto A.J., Moser A.J., Zeh H., Lee K., Bartlett D., McKolanis J.R., Geller B.A., Schmotzer A., Potter D.P., Whiteside T., et al. A phase I/II study of a MUC1 peptide pulsed autologous dendritic cell vaccine as adjuvant therapy in patients with resected pancreatic and biliary tumors. Cancer Ther. 2008;6:955-964.

    Not in our library

  117. 117.

    Miyazawa M., Ohsawa R., Tsunoda T., Hirono S., Kawai M., Tani M., Nakamura Y., Yamaue H. Phase I clinical trial using peptide vaccine for human vascular endothelial growth factor receptor 2 in combination with gemcitabine for patients with advanced pancreatic cancer. Cancer Sci. 2010;101:433-439.

    Not in our library10.1111/j.1349-7006.2009.01416.x

  118. 118.

    Suzuki N., Hazama S., Iguchi H., Uesugi K., Tanaka H., Hirakawa K., Aruga A., Hatori T., Ishizaki H., Umeda Y., et al. Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study. Cancer Sci. 2017;108:73-80.

    Not in our library10.1111/cas.13113

  119. 119.
    Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer · 2017
    No notice
  120. 120.

    Gilliam A.D., Broome P., Topuzov E.G., Garin A.M., Pulay I., Humphreys J., Whitehead A., Takhar A., Rowlands B.J., Beckingham I.J., et al. An international multicenter randomized controlled trial of G17DT in patients with pancreatic cancer. Pancreas. 2012;41:374-379.

    Not in our library10.1097/mpa.0b013e31822ade7e

  121. 121.

    Maki R.G., Livingston P.O., Lewis J.J., Janetzki S., Klimstra D., DeSantis D., Srivastava P.K., Brennan M.F. A phase I pilot study of autologous heat shock protein vaccine HSPPC-96 in patients with resected pancreatic adenocarcinoma. Dig. Dis. Sci. 2007;52:1964-1972.

    Not in our library10.1007/s10620-006-9205-2

  122. 122.

    Koido S., Okamoto M., Shimodaira S., Sugiyama H. Wilms’ tumor 1 (WT1)-targeted cancer vaccines to extend survival for patients with pancreatic cancer. Immunotherapy. 2016;8:1309-1320.

    Not in our library10.2217/imt-2016-0031

  123. 123.

    Morse M.A., Nair S.K., Boczkowski D., Tyler D., Hurwitz H.I., Proia A., Clay T.M., Schlom J., Gilboa E., Lyerly H.K., et al. The feasibility and safety of immunotherapy with dendritic cells loaded with CEA mRNA following neoadjuvant chemoradiotherapy and resection of pancreatic cancer. Int. J. Gastrointest. Cancer. 2002;32:1-6.

    Not in our library10.1385/ijgc:32:1:1

  124. 124.

    Carbone D.P., Ciernik I.F., Kelley M.J., Smith M.C., Nadaf S., Kavanaugh D., Maher V.E., Stipanov M., Contois D., Johnson B.E., et al. Immunization with mutant p53- and K-ras-derived peptides in cancer patients: Immune response and clinical outcome. J. Clin. Oncol. 2005;23:5099-5107.

    Not in our library10.1200/jco.2005.03.158

  125. 125.

    Kondo H., Hazama S., Kawaoka T., Yoshino S., Yoshida S., Tokuno K., Takashima M., Ueno T., Hinoda Y., Oka M., et al. Adoptive immunotherapy for pancreatic cancer using MUC1 peptide-pulsed dendritic cells and activated T lymphocytes. Anticancer Res. 2008;28:379-387.

    Not in our library

  126. 126.

    Koido S., Homma S., Okamoto M., Takakura K., Mori M., Yoshizaki S., Tsukinaga S., Odahara S., Koyama S., Imazu H., et al. Treatment with chemotherapy and dendritic cells pulsed with multiple Wilms’ tumor 1 (WT1)-specific MHC class I/II-restricted epitopes for pancreatic cancer. Clin. Cancer Res. 2014;20:4228-4239.

    Not in our library10.1158/1078-0432.ccr-14-0314

  127. 127.

    Jiang N., Qiao G., Wang X.-L., Morse M.A., Gwin W.R., Zhou L., Song Y., Zhao Y., Chen F., Zhou X.-N., et al. Dendritic Cell/Cytokine-Induced Killer Cell Immunotherapy Combined with S-1 in Patients with Advanced Pancreatic Cancer: A Prospective Study. Clin. Cancer Res. 2017;23:5066-5073.

    Not in our library10.1158/1078-0432.ccr-17-0492

  128. 128.

    Chmielewski M., Hahn O., Rappl G., Nowak M., Schmidt–Wolf I.H., Hombach A.A., Abken H. T Cells That Target Carcinoembryonic Antigen Eradicate Orthotopic Pancreatic Carcinomas Without Inducing Autoimmune Colitis in Mice. Gastroenterology. 2012;143:1095.e2-1107.e2.

    Not in our library10.1053/j.gastro.2012.06.037

  129. 129.

    Maliar A., Servais C., Waks T., Chmielewski M., Lavy R., Altevogt P., Abken H., Eshhar Z. Redirected T cells that target pancreatic adenocarcinoma antigens eliminate tumors and metastases in mice. Gastroenterology. 2012;143:1375-1384.

    Not in our library10.1053/j.gastro.2012.07.017

  130. 130.

    Posey A.D., Schwab R.D., Boesteanu A.C., Steentoft C., Mandel U., Engels B., Stone J.D., Madsen T.D., Schreiber K., Haines K.M., et al. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 2016;44:1444-1454.

    Not in our library10.1016/j.immuni.2016.05.014

  131. 131.

    Zhao Y., Moon E., Carpenito C., Paulos C.M., Liu X., Brennan A.L., Chew A., Carroll R.G., Scholler J., Levine B.L., et al. Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 2010;70:9053-9061.

    Not in our library10.1158/0008-5472.can-10-2880

  132. 132.

    Abate-Daga D., Lagisetty K.H., Tran E., Zheng Z., Gattinoni L., Yu Z., Burns W.R., Miermont A.M., Teper Y., Rudloff U., et al. A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer. Hum. Gene Ther. 2014;25:1003-1012.

    Not in our library10.1089/hum.2013.209

  133. 133.

    Tal Y., Yaakobi S., Horovitz-Fried M., Safyon E., Rosental B., Porgador A., Cohen C.J. An NCR1-based chimeric receptor endows T-cells with multiple anti-tumor specificities. Oncotarget. 2014;5:10949-10958.

    Not in our library10.18632/oncotarget.1919

  134. 134.

    DeSelm C.J., Tano Z.E., Varghese A.M., Adusumilli P.S. CAR T-cell therapy for pancreatic cancer. J. Surg. Oncol. 2017.

    Not in our library10.1002/jso.24627

  135. 135.

    Nywening T.M., Wang-Gillam A., Sanford D.E., Belt B.A., Panni R.Z., Cusworth B.M., Toriola A.T., Nieman R.K., Worley L.A., Yano M., et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: A single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol. 2016;17:651-662.

    Not in our library10.1016/s1470-2045(16)00078-4

  136. 136.

    Chen J., Xiao-Zhong G., Qi X.-S. Clinical Outcomes of Specific Immunotherapy in Advanced Pancreatic Cancer: A Systematic Review and Meta-Analysis. J. Immunol. Res. 2017.

    Not in our library10.1155/2017/8282391

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