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The Tumor Microenvironment of Epithelial Ovarian Cancer and Its Influence on Response to Immunotherapy

Galaxia Rodriguez, Kristianne Galpin, Curtis McCloskey and 1 more

Cancers · 2018 · Review · CC BY

Abstract

Immunotherapy as a treatment for cancer is a growing field of endeavor but reports of success have been limited for epithelial ovarian cancer. Overcoming the challenges to developing more effective therapeutic approaches lies in a better understanding of the factors in cancer cells and the surrounding tumor microenvironment that limit response to immunotherapies. This article provides an overview of some ovarian cancer cell features such as tumor-associated antigens, ovarian cancer-derived exosomes, tumor mutational burden and overexpression of immunoinhibitory molecules. Moreover, we describe relevant cell types found in epithelial ovarian tumors including immune cells (T and B lymphocytes, Tregs, NK cells, TAMs, MDSCs) and other components found in the tumor microenvironment including fibroblasts and the adipocytes in the omentum. We focus on how those components may influence responses to standard treatments or immunotherapies.

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From PubMed Central, U.S. National Library of Medicine, as current on Oct 25, 2026. Paragraph numbers are ours, so an answer can point at one.

1. Introduction

1An increasing body of evidence strongly suggests that the immune system is able to identify, control and eliminate nascent neoplastic cells in a process known as cancer immunosurveillance. Epithelial ovarian cancers (EOCs) are “immunogenic tumors” that produce spontaneous antitumor immune responses detectable in peripheral blood, tumors and ascites of patients. The resulting presence of tumor infiltrating lymphocytes (TILs) is associated with improved survival in EOC. Unfortunately, there are a number of factors in the tumor microenvironment (TME) that can impair the presence or activity of TILs, thereby facilitating cancer progression.

2Various immunotherapeutic strategies are attempting to address the challenges posed by the highly immunosuppressive EOC TME. Immunotherapies encompass many modalities, including immune checkpoint blockade, antibody-based therapies, cancer vaccines, cytokines, adoptive cell transfer, and chimeric antigen receptor-modified T cells. However, emerging cancer immunotherapies (blocking antibodies for checkpoint inhibitors) have shown low rates of responses in EOC (reviewed in). Improving this response rate is a major goal, which can only be achieved with a better understanding of the elements in the TME that contribute to treatment failure. Immune cells are the main players in the development of antitumor immunity or tumor progression, but there are also other components in the TME that should be taken into consideration when designing new therapeutic strategies. Those components include EOC-derived exosomes, cancer-associated fibroblasts (CAFs) and adipocytes residing in the omentum.

3In this review we will describe those elements of the TME, how they influence the burden of the tumor, the responses to therapies, and their relevance in designing cancer immunotherapies for EOC.

2. Cancer Cells and Tumor Antigens

4The success of cancer immunotherapy hinges on the ability to generate cancer-specific antitumor T-cell responses, to both recognize tumor-associated antigens (TAAs) and kill tumor cells, and to generate memory responses. TAAs can be classified into different categories: tissue differentiation, cancer testes antigens (CTAs), neoantigens derived from mutations, overexpressed cellular, splice variant, glycolipid, and viral antigens. Ideal TAAs for immunotherapy targets are immunogenic and are expressed or overexpressed in tumor tissue, with restricted expression in associated normal tissues, in a significant percentage of patients. Positive responses to immunotherapies such as immune checkpoint inhibitors [blocking programmed cell death protein 1 (PD-l), programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4)], have been associated with high mutation/neoantigen burden. The initial clinical studies of small numbers of EOC patients treated with immune checkpoint inhibitors have resulted in clinical benefits in less than 20% of patients (Table 1). Unfortunately, little is known about the TME at the start of treatment in most studies, making it impossible to discern the factors that may have blocked any response. The failure to respond could be related to the neoantigen burden in EOC, which may be insufficient to generate a significant antitumoral response. There are currently intense research efforts to understand other TAAs (Table 2) recognized by TILs to design informed immunotherapy targets (Table 3).

2.1. Neoantigens

5Ovarian cancer has been shown to harbor an intermediate neoantigen load by whole exome sequencing/next generation sequencing. Whole exome sequencing of tumor cells from ascites samples of three high-grade serous ovarian cancer (HGSC) patients revealed a tumor mutation burden (TMB) of approximately 20–40 mutations across all patients, however only 1/79 mutations (1.3%) were recognized by autologous tumor-associated T cells. Comprehensive genomic profiling of ovarian cancer revealed low overall TMB among subtypes: HGSC (3.6), low-grade serous (LGSOC) (2.7), endometrioid (2.7), mucinous (2.7), and clear cell (2.7). Only a small percentage of patients had a significant TMB (20 or more mutations per Mb), meaning only a small percentage of patients would be predicted to show favorable response to immune therapy. Consequently, in clinical trials of checkpoint inhibitors in EOC, CTLA-4 inhibitors (Ipilimumab), PD1 inhibitors (Nivolumab and Pembrolizumab), and PD-L1 inhibitors (MS-936559 and Avelumab) had response rates of 5–20% (Table 1). A notable exception is the highly aggressive small cell carcinoma of the ovary, hypercalcemic type which, despite being a monogenic cancer, has responsiveness to anti-PD1 immunotherapy.

6Neoantigen depletion, intratumoral heterogeneity, and clonal evolution of primary tumors and metastases may influence immunosurveillance and response to immunotherapy. Epithelial T-cell rich tumors show the lowest amount of clonal diversity, neoantigen diversity and greatest loss of human leukocyte antigen (HLA) expression, which suggests immunoediting in the TME. T-cell poor tumors or “cold tumors” have a higher predicted and more diverse neoantigen load (unedited).

2.2. Cancer Testes Antigens

7CTAs are encoded by ~140 genes that are normally only expressed in germ cells (testes, placenta, fetal ovary) and not normal somatic adult cells, but often highly expressed in tumors. This along with their immunogenicity makes them significant targets for cancer immunotherapy. Vaccination with recombinant MAGE-A3 antigen has been used in Phase I/II clinical trials for melanoma and non-small-cell lung cancer (NSCLC) with a good safety profile and observed humoral response, but only slight effects on survival.

8Several CTAs have been described in EOC (Table 2) and have been proposed as immunotherapy targets (Table 3) based on their tissue specificity and high expression in a significant number of EOCs of all subtypes. NY-ESO-1 (ESO157–165) specific CD8+ T cells were found in TILs of 71% of (10/14) vaccination naïve seropositive patients, and ex vivo proliferation of NY-ESO-1 specific peripheral blood lymphocytes in 65% of patients suggested that an adaptive immune response against this CTA can be achieved. Clinical trials have subsequently tested the feasibility of generating NY-ESO-1 specific immune responses (Table 3). These approaches have generated humoral and CD4+ and CD8+ antigen specific T-cell responses, and in some cases, long lasting/complete responses. NY-ESO-1 was not expressed in some recurrent tumors, raising the possibility of immune escape. Furthermore, NY-ESO-1 reactive CD8+ T cells often express higher levels of inhibitory molecules lymphocyte-activation gene 3 (LAG3), PD-1 and CTLA-4, suggesting immunosuppression as a reason for lack of complete response during clinical trials.

9Many characteristics of CTA epitopes and all TAAs such as (i) immunogenicity; (ii) restriction to HLA-I or -II; (iii) natural processing; (iv) expression; and (v) role in tumor progression remain to be elucidated and require validation in larger sample sizes. While the expression of CTAs does not often correlate with improved survival, their tissue specificity makes CTAs attractive targets for immunotherapies (Table 3) such as peptide vaccines, antigen-loaded dendritic cell (DC) vaccines, or oncolytic viral platforms, and for combined interventions with immune checkpoint inhibitors or chemotherapy, in order to overcome tumor escape mechanisms.

2.3. Other TAAs

10Genetic and epigenetic aberrations in cancer cells, resulting from mutations, amplifications or deletions in genes, provide both therapeutic targets and potential TAAs for immunotherapy design (Table 2). However, the greatest hurdles still remain in designing immunotherapeutic targets for a disease in which such aberrations, with the exception of p53 mutation (95% of HGSC), are relatively uncommon (<20% frequency in HGSC cases) and lack antigen specificity to the tumor. Immunogenic oncogenes p53, Her2-neu and WT1 are broadly overexpressed in EOC, particularly HGSC, and targeted immunotherapies have been explored in clinical trials (Table 3). Other common but infrequent amplifications, mutations or deletions occur in CCNE1, NF1, PTEN, KRAS, RB, CDK2NA, PIK3CA and AKT1/2 and provide potential therapeutic targets for EOC immunotherapy. The DCs, T-cells, and peptide-based vaccine strategies against proteins described above have largely demonstrated immunological responses including CD4+ and CD8+ T-cell responses in preliminary clinical trials following vaccination, but often in the absence of clinical responses. This is perhaps due to widespread immunosuppression in the TME preventing T-cell activation and proliferation, as well as tumor heterogeneity and immunogenicity that impede proper TAA presentation to the immune cells.

11The EOC immunopeptidome was profiled by isolating HLA molecules primarily from HGSC tumors and which were analyzed by mass spectrometry. The analysis identified relevant proteins including CRABP1/2, FOLR1, and KLK10 presented on major histocompatibility complex (MHC) I molecules, and mesothelin, PTPRS and UBB presented on MHC-II molecules. The most abundantly detected protein presented on MHC-I molecules was MUC16 (CA-125), with 113 different peptides expressed in approximately 80% of patients. MUC16-derived peptides were highly immunogenic (85% T-cell responses in vitro), and consequently it was proposed as the top candidate for targeted immunotherapy moving forward. Although CA-125 is immunogenic, the large number of trials with a monoclonal antibody targeting CA-125 (Table 3) have been mostly unsuccessful as a monotherapy. This failure could be explained by the weak magnitude of the immune response generated, the loss of expression or down-regulation of CA-125 on EOC cells to avoid immune recognition, or the overgrowth of CA-125 EOC cells as a consequence of cancer immunoediting process.

12A single TAA is generally only expressed in a subset of patients, making the design of a universal immunotherapy challenging. The main barrier of targeting a single TAA is cancer immunoediting, which enables the enrichment of neoplastic cells in tumors that do not express the targeted TAA over time. Chimeric antigen receptor T (CAR-T) cells provides the option of combining multiple antigen specificities, and delivering direct cytokine stimulation (GM-CSF, IL-12) to the TME, irrespective of the MHC status of the patient.

2.4. Tumor Immunogenicity and Other Immunoinhibitory Molecules

13Loss of immunogenicity is an immune hallmark of cancer that is exploited by tumors to evade immune recognition. This can be triggered by down-regulation or loss of expression of MHC-I and -II, and the antigen processing and presentation machinery (APM). Expression of MHC-I genes is altered by 60–90%, depending on the cancer type. These impairments reduce the antigens presented on the cell surface leading to decreased or lack of recognition and elimination by cytotoxic T lymphocytes.

14The mechanisms that are related to immune cell infiltration in EOC are dependent on MHC-I and -II status. The presence of neoantigen-reactive T cells in patients with EOC can improve survival. However, as mentioned before, since ovarian tumors possess intermediate/low mutation burdens, the incidence of naturally processed and presented neoantigens generating a significant antitumoral response is very low. The expression of APM components and the presence of intratumoral T-cell infiltrates were significantly associated with improved survival. Han. et al. demonstrated that the majority of ovarian carcinomas analyzed had either heterogeneous or positive expression of peptide transporter 1 (TAP1), TAP2, HLA class I heavy chain, and beta-2 microglobulin. Concurrent expression of HLA-DR and CA-125 on cancer cells correlated with higher frequency of CD8+ TILs and increased survival. Similarly, tumor cell expression of HLA-DMB was associated with increased numbers of CD8+ TILs and both were associated with improved survival in advanced-stage serous EOC. The regulation of APM components and MHC molecules in human cancers is a significant area of research but is beyond the scope of this review (reviewed in).

15The mutational profile of EOC can also predict immunogenicity. Tumors with deficient homologous recombination (HR) machinery occur with a frequency of up to 50%. These include mutations in BRCA1/BRCA2 (20% frequency) or non-BRCA HR deficiencies (Fanconi anemia genes, restriction site associated DNA genes, and DNA damage response genes). HR deficient tumors have higher predicted neoantigen load, and infiltrating and peritumoral lymphocytes in these tumors have increased PD-1/PD-L1 expression, which may enhance susceptibility to immune checkpoint therapy. BRCA1/2 mutated HGSC tumors have more CD3+ and CD8+ TILs compared to HR-proficient tumors, a signature associated with higher overall survival. p53 mutations are also associated with higher levels of TILs. Non-HR deficient tumors therefore have poorer overall survival and may be less immunogenic, making them more difficult to target with immunotherapies. Alternative strategies and TAAs to target this group of EOC tumors need further investigation.

16The expression of immunoinhibitory molecules on cancer cells, including PD-L1 and Indoleamine 2,3-dioxygenase (IDO) are associated with patient prognosis. Higher expression of PD-L1 on tumor cells correlates with poorer prognosis, suggesting that the PD-1/PD-L pathway can be a good target for restoring antitumor immunity in EOC, although others have suggested that high PD-1/PD-L1 expression in primary tumors may be associated with a favorable progression-free survival. Increased infiltration of CD8+ T cells is associated with high PD-L1 expression likely as a result of an adaptive response where infiltrating CD8+ T cells secrete interferon gamma (IFNγ) that subsequently induces PD-L1 expression on cancer cells. This in turn inhibits T-cell activation and proliferation, preventing successful targeting and clearance of the tumor. Immune checkpoint inhibitors (anti-PD-L1 and PD-1) have been FDA approved for melanoma and NSCLC, but only a small percentage (10–33%) of ovarian cancers express PD-L1, thus only a small percentage of patients may respond to anti-PD-L1 immunotherapy (Table 1). The enzyme IDO is often overexpressed by cancer cells, but is also produced by DCs and macrophages in the TME. IDO catabolizes tryptophan, which leads to cell cycle arrest or apoptosis in NK and CD4 T cells, and skewed differentiation of regulatory T cells (Tregs) induced by plasmacytoid DCs, leading to immunosuppression in the TME. Positive staining for IDO, observed in 24–57% of patient samples, is associated with poor prognosis of HGSC, decreased CD8+ TILs, as well as resistance to chemotherapy. Targeting IDO with inhibitors may improve outcome.

3. Immune Cells

17Most solid tumors are infiltrated by myeloid- and lymphoid lineage-derived immune cells that are differentially distributed within the TME with a crucial role in the establishment of antitumoral responses or tumor progression. Growing tumor cells release “danger signals” that enable the recruitment of immune cells into the tumor niche. TILs such as CD4+ and CD8+ T cells, B lymphocytes, Natural Killer (NK)-T cells, as well as innate immune cells such as NK cells, macrophages and DCs, are then recruited in order to eliminate nascent neoplastic cells, acting as an extrinsic tumor suppression mechanism. However, immunosurveillance promotes the selection of poorly immunogenic cancer cells through cancer immunoediting where neoplastic cells that resist the elimination phase can persist in equilibrium with effector CD4+ and CD8+ T cells under a pro-inflammatory milieu. Over time, cancer cells with the most immunoevasive characteristics are selected, enabling them to eventually escape immune attack. Finally, immunoedited tumors become clinically apparent with variants that trigger the establishment of an immunosuppressive TME containing immunosuppressive immune cells such as myeloid-derived suppressor cells (MDSCs), Tregs, and others.

3.1.1. TILs

18TILs can localize into the tumor islet (intraepithelial) and in the peritumoral space (stromal). Several studies have shown a positive correlation between the presence of intraepithelial TILs and tumor regression in many solid cancers. T cells can be found in primary tumor tissue and omental metastases and their presence has been correlated with positive prognosis. Dadmarz et al. demonstrated that TILs isolated from EOC patients (primary tumor, metastases or ascites) were tumor-specific and could recognize autologous TAAs. Antitumoral responses were mainly characterized by the secretion of tumor necrosis factor-alpha (TNFα) and granulocyte macrophage-colony stimulating factor (GM-CSF) when stimulated with autologous tumor. Later, Zhang and colleagues showed that intraepithelial CD3+ TILs can be found in >50% of advanced-stage EOC with their presence correlating with a five-year overall survival rate of 38% in contrast to 4.5% in patients whose tumors contained no T cells. Even after debulking and platinum-based chemotherapy, the presence of intraepithelial CD3+ TILs increased the five-year overall survival rate (>70%) in comparison to patients whose tumors contained no T cells in islets (11%). T cell-rich tumors correlated with delayed recurrence or death and were associated with increased expression of Interleukin-2 (IL-2), IFNγ and lymphocyte-attracting chemokines within the tumor such as CXCL9, CCL21, and CCL22. Conversely, tumors with no T cells in islets were associated with an increased level of vascular endothelial growth factor (VEGF), an angiogenic regulatory factor in the TME associated with early recurrence and short survival. A more recent study showed that intratumoral accumulation of CXCR3 ligands such as CXCL9 and CXCL10, predicts survival in advanced HGSC (Figure 1). This study also identified the cyclooxygenase (COX) metabolite Prostaglandin E2 as a negative regulator of chemokine secretion that contributes to tumor progression by impeding TILs recruitment in ovarian cancer. Further investigation showed that expression of both COX-1 and COX-2 were negatively correlated with intraepithelial CD8+ TILs as well as with EOC patient survival.

19While some studies have reported that the presence of both intraepithelial CD3+ and CD8+ T-cells correlates with improved disease-specific survival for EOC patients others have shown that this beneficial characteristic is attributed to intraepithelial CD8+ TILs. No association was found for CD3+ TILs or other subtypes of intraepithelial or stromal TILs in EOC overall patient survival. Interestingly, the subgroups displaying high versus low intraepithelial CD8+/CD4+ TIL ratios had favorable survival prognosis (median = 58 versus 23 months). This was due to the unfavorable effect of CD4+ CD25+ forkhead box P3+ (FOXP3) Tregs that will be discussed later.

20In 2012, a meta-analysis of ten studies with 1815 ovarian cancer patients confirmed the prognostic value of intraepithelial CD8+ TILs in EOC specimens regardless of the tumor grade, stage, or histologic subtype studied. Their presence suggests that spontaneously activated antitumoral responses are present in the tumor niche to control tumor outgrowth as observed by the presence of tumor-reactive antibodies and T cells found in the peripheral blood of advanced stage EOC patients, and oligoclonal tumor-reactive T cells isolated from blood, ascites or tumors. Conversely, the lack of intraepithelial TILs is significantly associated with poor survival among EOC patients. Thus, immunotherapies aiming to increase the effector functions of pre-existing antitumoral CD8+ TILs and triggering effector T cell-trafficking to the TME are the holy grail of cancer immunotherapy.

21CD4+ T cells as well as CD8+ T cells can specifically recognize TAAs from malignant cells. CD4+ T helper (Th) cells provide cytokine support for CD8+ T-cell proliferation and expansion to eliminate cancer cells and trigger antitumoral responses. In an analysis of ovarian tumors, Tsiatas et al. found that a high percentage of CD4+ CD25hi cells and activated CD4+ T cells were significantly associated with improved median overall survival. Two other studies also showed a positive correlation of the high frequency of CD4+ TILs and EOC patient survival. Nesbeth et al., using an animal model for EOC, found that tumor-primed CD4+ T cells produce high levels of CCL5 that enables the recruitment and activation of DCs to the TME. Mature DCs were then able to prime tumor-specific CD8+ T cells and confer long-term protection. Hence, immunotherapies stimulating both effector CD4+ and CD8+ T cells could confer synergistic antitumoral responses.

3.1.2. Regulatory T lymphocytes

22Tregs negatively regulate antitumoral responses in both a direct and indirect manner, highlighting that Tregs are a fundamental means of tumor immune evasion. In healthy tissues, Tregs mediate tolerance by suppressing autoreactive T cells to protect and prevent excessive tissue destruction. Since most TAAs are composed by self-peptides, Tregs are often found in tumors to dampen antitumoral responses. Tregs accumulate and are more frequently present in tumors, with a shift in the median ratio of Tregs to TILs from 3–8% in healthy tissue to 18–25% in all analyzed cancers, including EOC. Curiel et al. analyzed 104 EOC specimens and found that CD4+ CD25+ FOXP3+ Tregs specifically suppress antitumoral T cells in vivo, contributing to tumor growth. In addition, their presence correlates with poor patient outcome. CD4+ Tregs preferentially migrated to tumor and ascites and were rarely found in draining lymph nodes at later cancer stages. Immunotherapies impeding Treg trafficking could release the TME immunosuppression and promote the development of antitumoral responses.

23FOXP3+ Tregs express minimal levels of effector cytokines and granzyme B, but are able to induce inhibitory activities through IL-10 and transforming growth factor beta (TGF-β) production and cell–cell interactions (Figure 2). Barnett et al. showed that EOC tumors highly infiltrated by Tregs were associated with poor survival, advanced stage and suboptimal debulking. Investigation of the influence of cytoreduction on the immune system of primary and recurrent EOC found that the ratio of CD4/CD8 is increased in primary but not in recurrent tumors. Primary cytoreduction increased circulating effector CD4+ and CD8+ T cells, but circulating CD4+ Tregs were decreased as well as IL-10 serum levels, but not TGFβ and IL-6. CD4+ Tregs were also decreased after chemical debulking in patients treated with neoadjuvant chemotherapy. The reduction of the systemic and TME immunosuppression triggered by surgical debulking resulted in an increased capacity of CD8+ T cells to respond to the recall antigens, but not in patients who were previously subjected to chemotherapy or affected by recurrent EOC.

24Fialová and colleagues studied the dynamics of the tumor-infiltrating immune cells during different stages of EOC. Early stage disease displayed a strong Th17 immune response while stage II patients had responses characterized by the recruitment of Th1 cells. Disseminated disease (stages III and IV) were characterized by high amounts of Tregs, tumor-associated macrophages (TAMs), DCs, and high levels of CCL22, which is secreted by tumor cells, TAMs and DCs to enable further recruitment of Tregs and immunosuppression. Other studies have shown the importance of the TME in facilitating the establishment of tolerance and recruitment of Tregs to sustain tumor growth. Using EOC cell lines in vitro, Facciabene et al. found that tumor hypoxia induces the expression of chemokine ligands such as CCL28, enabling the recruitment of Tregs and triggering angiogenesis. CCL28 overexpression was associated with a poor outcome in patients with EOC. Similarly, CCL22 production by TAMs enabled the recruitment of Tregs that induced B7-H4 on antigen-presenting cells including macrophages. CXCR3+ Tregs, able to control type-I T-cell responses, are highly enriched in EOC and represent the majority of Tregs. These Tregs were able to suppress T-cell proliferation and IFNγ secretion.

25An interesting study analyzed 22 EOC ascites specimens and found significantly elevated levels of IL-6, IL-8, IL-10, IL-15, IP-10, MCP-1, MIP-1β and VEGF and significantly reduced levels of IL-2, IL-5, IL-7, IL-17, PDGF-BB, and CCL5 compared to plasma. Moreover, T cells derived from EOC-associated ascites displayed poor responsiveness when expanded in vitro. The authors claimed that this non-responsiveness could be explained by a high CD4/CD8 ratio that may indicate the presence of Tregs, reduced IL-2 and elevated IL-6 and IL-10 levels triggering a Th2 inhibitory immune response. This high CD4/CD8 ratio was also associated with poor outcome, consistent with other studies. In contrast, a positive correlation between Tregs and patient prognosis has been reported. High tumor grade correlated with higher frequencies of CD3+, CD68+ CD163+ TAMs, and CD25+ FOXP3+ Treg cells, but Treg frequencies were significant predictors of favorable prognosis in patients with familial ovarian cancer (11/73 patients with BRCA mutation). The presence of FOXP3+ TILs may be linked to positive prognostic factors in optimally debulked HGSC patients. Nevertheless, this disease-specific survival was positively associated along with other TIL markers such as CD8, CD3, TIA-1, CD20 (a B cell surface marker), MHC class I and class II.

26CD8+ Tregs are also found in EOC. They regulate the immunosuppressive TME by limiting immunosurveillance mechanisms and contributing to cancer progression. Recently, Zhang and colleagues showed that CD8+ Tregs are found in the stroma and intraepithelial areas of EOC tumors. CD8+ Tregs are characterized by the expression of FOXP3, CTLA-4, and CD25, but decreased expression of CD28. CD8+ Tregs were able to convert effector CD8+ T cells into suppressor cells. CD8+ Tregs exert their suppressive function through the secretion of TGF-β1.

27Overall, Tregs are considered a critical barrier against antitumoral responses along with tolerance-inducing plasmacytoid DCs, B7-H4+ TAMs, MDSCs, IL-10, TGFβ, and VEGF. All these processes act in concert as a tumor evasion mechanism resulting in tumor progression. Barriers to antitumoral responses are summarized in Figure 2.

3.1.3. B Lymphocytes

28B lymphocytes have been reported to have pivotal roles in cancer immunity. Stromal or intraepithelial B lymphocytes have been found in EOC; however their function in tumor development is not yet clear. Their presence is proposed to be associated with a good prognosis depending on the tumor stage and the TME where they are found. The presence of B cells and CD8+ TILs correlates with increased patient survival compared to CD8+ TILs alone. Nielsen et al. analyzed tumor and serum specimens obtained from patients with HGSC and found that the majority of CD20+ TILs were antigen experienced and suggested to accomplish TAA presentation in the TME since they often co-localized with CD8+ TILs and expressed markers such as MHC-I, MHC-II, CD40, CD80, and CD86. B cells can achieve antitumor immunity by secreting IFNγ, facilitating CD4+ Th cells to polarize to Th1 responses, and promote T-cell expansion by presenting TAAs. Recently, the positive role of B cells among TILs at metastatic sites from patients with HGSC was reported. B cells were often found in the stroma of metastases and were characterized by a strong memory response against TAAs by production of tumor-specific IgGs (Figure 1). Interestingly, these responses were amplified by chemotherapy.

29Conversely, a new subset of B cells, regulatory B cells (Bregs), has been recently designated as immunosuppressive cells able to secrete anti-inflammatory mediators such as IL-10, IL-35, and TGF-β, triggering T-cell conversion to Tregs (Figure 2). Indeed, a study that analyzed EOC tumor tissue and omental metastases found that high B cell infiltration negatively correlates with patient survival. High CD20 and CD138 expression correlated with high tumor grade. Analysis of omental specimens from patients with HGSC found that overall survival was 160.6 months in patients with low B-cell expression vs. 47.3 months in those with high B-cell expression, associating increased B-cell infiltration with poorer survival. Similarly, the analysis of post-chemotherapy effusions from ovarian carcinomas revealed that a higher percentage of CD19+ cells (B cell marker) and stage IV disease predicted poor survival for patients.

30Taken together, it is important to consider that several B-cell subsets with different phenotypes and functions exist, and they may have various roles in modifying the ability of tumors to respond to treatment. Thus, a deep characterization of B-cell subpopulations within the TILs, ascites, and peripheral blood at different stages is crucial in order to provide a better understanding of the capability, importance and therapeutic potential of these cells in EOC.

3.1.4. NK-T Lymphocytes

31NK-T cells possess dual-functional capability: as T-cell subsets with a T-cell receptor (TCR)-mediated specific cytotoxicity and as NK cells with acquired killer functions. NK-T cells have been found in increased frequencies in EOC tumor ascites compared to blood, but they were decreased at higher tumor grade and in cases of platinum resistance. Moreover, the presence of NK-T cells was inversely correlated with VEGF ascites levels. Since these cells display the most potent cytotoxicity profile, they might be promising agents for adoptive cell immunotherapy. Further studies are needed to better understand the potential antitumoral capacity of these cells and their role in the different EOC TMEs.

3.2.1. NK Cells

32Many studies have reported the presence of innate immune cells such as NKs, macrophages and DCs playing important roles in EOC tumorigenesis. NK cells are crucial effectors in cancer immunosurveillance, recognizing and spontaneously killing virus-infected cells, cancer, and foreign cells hazardous to the host. NK cells mediate antitumoral responses by secreting pro-inflammatory cytokines and chemokines such as IFNγ, TNF, IL-6, GM-CSF and CCL5, which influence antitumor activity and promote innate and adaptive responses in the TME (Figure 1). Tsiatas et al. analyzed 45 fresh specimens from different EOC and found an increased amount of CD56+ NK and NK-T cells along with activated CD4+ and CD8+ CD25+ T cells in serous and endometrioid carcinomas compared with mucinous and clear cell carcinomas. Despite the high concentration of NKs found in ascites compared to peripheral blood, they are functionally impaired. The influence of infiltrating NK cells on patient outcome is also debated. Analysis of ovarian carcinoma effusions showed that the presence of NK cells at an advanced stage (IV) predicted worse overall survival. However, a positive antitumoral role for NK cells along with effector CD8+ T cells has been reported, and NK cell activity of peripheral blood lymphocytes was related to a significant progression-free survival of EOC patients. Importantly, NK cells are activated or not, according to the balance between inhibitory and activating signals through different NK receptors. Like many other cancers, EOC tumors express NK cell receptor ligand ULBP2, which is an indicator of poor prognosis and could promote T-cell dysfunction in the TME (Figure 2). Since NK cells are important players in antitumoral immunity, more studies aiding to characterize their function, phenotypes, incidence and role in the EOC TME are needed to provide new rational for immunotherapies.

3.2.2. Tumor-Associated Macrophages

33Both TAMs and MDSCs constitute up to 20% of the EOC TME and are known to maintain and promote an immunosuppressive TME (Figure 2). TAMs are considered the most abundant infiltrating immune cells in EOC tissue and ascites. They possess an immunosuppressive M2 phenotype characterized by the expression of CD163, CD204, CD206, and IL-10, and their presence correlates with tumor progression. M2 TAMs secrete colony-stimulating factor 1 (CSF-1) that has been found in high levels in malignant EOC, and contributes to tumor growth, invasion, and metastasis. Moreover, EOC cells are able to induce an M2 TAM phenotype. TAMs produce the chemokine CCL22 enabling the trafficking of Tregs to the ovarian tumors. EOC cells as well as TAMs are known to express the coinhibitory molecule B7-H4, a member of the B7 family that has a profound inhibitory effect on the growth, cytokine secretion, and development of T-cell cytotoxicity. B7-H4+ TAMs are able to suppress antitumoral responses in EOC. A study of 103 EOC patients showed that enhanced B7-H4 expression in macrophages correlated with Treg cell numbers in the tumor. Tregs and B7-H4+ TAMs were associated with poor patient outcome. Tregs in the TME can induce B7-H4+ TAMs to produce IL-10 and IL-6, further supporting an immunosuppressive milieu. Higher tumor grade correlated with higher frequencies of CD163+ TAMs and worse progression-free survival. Importantly, two studies evaluating M1- (HLA-DR, iNOS) and M2-polarization (CD163, VEGF) markers showed that higher M1/M2 TAMs ratio in tumors was associated with a favorable overall survival, and high serum levels of CD163 predicts poor EOC patient prognosis. In addition, monocyte-derived macrophages in EOC displayed an altered morphology and defective antitumoral functions including defective antibody-dependent cell-mediated cytotoxicity and phagocytosis. Thus, EOC cells and the TME provoke and maintain a strong immunosuppressive M2 phenotype supportive of tumor progression. Immunotherapeutic approaches aiming to switch TAM phenotypes could help the evolution of antitumoral responses and improve patient outcome.

3.2.3. Myeloid-Derived Suppressor Cells

34MDSCs are composed of a heterogeneous population of immature myeloid cells that arise in pathologic conditions such as cancer, inflammation and infection, and possess a potent capacity to dampen T-cell responses. MDSCs are considered key inducers of tumor immune evasion and impaired immunity by upregulating arginase-1, nitric oxide, and reactive oxygen species, and by generating reactive nitrogen species (Figure 2). MDSCs also deplete cysteine, induce Tregs, inhibit T-cell activation and proliferation, attenuate the cytolytic ability of NK cells, and trigger a M2 phenotype. Obermajer et al. showed that the frequencies of CD11b+ CD14+ CD33+ CXCR4+ MDSCs in EOC ascites correlated with CXCL12 and prostaglandin E(2) levels. MDSCs derived from EOC patients also increased gene expression of cancer stem cells, sphere formation and metastasis of EOC. Wu et al. characterized typical monocytic CD14+ HLA-DR-/lo MDSCs in peripheral blood and ascites derived from EOC patients and found that MDSCs are enriched in both compartments. Moreover, the density of MDSCs correlated with poor patient prognosis and elevated levels of IL-6 and IL-10. VEGF expression in EOC induced MDSCs recruitment, inhibiting local immunity. A recent study with mouse EOC cells found that Snai1, a major transcription factor that induces epithelial-mesenchymal transition (EMT), mediates EOC progression by upregulating CXCR2 ligands, enabling the recruitment of MDSCs. EOC cells also attracts myeloid cells by producing adenosine. Hence, strategies targeting MDSCs could release the brakes against antitumoral responses. Metformin, a drug used to treat type 2 diabetes, may trigger EOC clinical benefit by improving antitumoral T-cell responses that are impeded by MDSCs in the TME, since this drug can block MDSC suppressor functions by decreasing CD39 and CD73 expression.

4. Exosomes

35Highly proliferating cells such as cancer cells produce large amounts of exosomes which are small (40–100 nm) extracellular vesicles. EOC tumor-derived exosomes carry cell membrane proteins and cargo proteins that could be used for diagnostics (EP-CAM) and immunotherapeutic targeting such as neoantigens and TAAs (Her2-neu, CA-125), proteins (TGF-β1), and miRNAs (miR-21) that are involved in disease progression, metastasis, and chemoresistance, as well as immunomodulatory proteins (FAS-L). Exosomes can be taken up by other cancer cells, CAFs, and immune cells, therefore playing an important role in intercellular communication. Thus far, 2035 exosome cargo molecules have been identified from EOC cells in ExoCarta, a database for exosome cargo. Exosomes derived from human patient ascites promotes tumor progression in vivo, and are proposed to have direct and indirect roles in modulating the immune TME, as exosomes could also be taken up by NKs and B cells (Figure 2). In other disease models, such as melanoma and colorectal cancer, exosomes mediate immunosuppression and immune tolerance by suppressing the activation of T and NK cells, monocytes, modulating T-cell inhibitory molecules expression, and inducing CD8+ T-cell apoptosis. FAS-L and TRAIL expression on EOC-derived exosomes inhibit activation of peripheral blood mononuclear cells by DCs through induction of apoptosis. EOC-derived exosomes express ligands (MICA/B and ULBP1-3) for the NK receptor NKG2D, acting as a decoy and interfering with NK-mediated targeting of tumor cells. Greater understanding of the complex network of the intercellular communication between EOC cells, CAFs, and immune cells is needed for the rational design of immunotherapeutic interventions, or leveraged for nanomedicine applications such as TAA loaded-DC-derived exosomes and drug delivery systems.

5. Cancer-Associated Fibroblasts

36CAFs are activated fibroblasts that express α-smooth muscle actin and fibroblast activation protein. They make up 7–85% of the tumor and are the primary stromal cell type in the TME. Cross-talk between epithelial and stromal compartments creates a positive feedback loop, a supportive hyper-activated storm of cytokines, chemokines, angiogenetic factors, and EMT-promoting factors, to promote tumor progression and chemoresistance (Figure 2). CAFs from ovarian cancer patients secrete high levels of hepatocyte growth factor (HGF) that promotes cancer cell proliferation, chemoresistance, invasion, and migration though constitutive activation of cMet/PI3K/Akt pathways and glucose-regulated protein 78 (GRP78). CAFs produce pro-inflammatory cytokines COX-2 and CXCL1, CCL5, CXCL11, and IL-6, which can promote proliferation and EMT. In addition to their direct actions on cancer cells, CAFs also produce exosomes with high levels of TGF-β1 that subsequently activates normal fibroblasts. Interestingly, Givel et al. identified four CAFs subsets in HGSC, finding an accumulation of one subset, CAF-S1, in the mesenchymal molecular subtype of HGSC. CAF-S1 is associated with an immunosuppressive TME, due to its high levels of expression of CXCL12β, which recruits Tregs to the tumor. The CAF-S1 cells also express CD73, B7-H3 and IL-6, which subsequently promote survival and proliferation of Tregs. Thus, CAFs can make major contributions to the creation of an immunosuppressive TME.

37On the other hand, EOC cells can stimulate the activation of CAFs by producing high levels of interleukin-1β (IL-1β) and TGF-β, which subsequently induces secretion of IL-8, IL-6, IL-1β, VEGF, and growth regulated oncogene-alpha (GRO-α) by CAFs to promote tumor progression. EOC cells release exosomes not only to activate tumor cells, but also to reprogram normal fibroblasts into CAFs. Furthermore, CAFs act on endothelial cells via the secretion of VEGF-C or by upregulating genes such as lipoma-preferred partner, to promote angiogenesis, which leads to tumor progression and chemoresistance. Cross-talk between CAFs and cancer cells, as well as endothelial cells and immune cells, suggests that targeting signaling mechanisms in this relationship may combat chemoresistance and immune modulation better than singly targeting the epithelial compartment.

6. Adipocytes and the Omentum

38The unique TME of the omentum, a large visceral fat pad that covers the bowel and abdomen cavities, suggests a two-step model of omental metastasis and tumorigenesis where ovarian cancer cells preferentially and rapidly home to “milky spots” in the omentum, prior to spreading throughout non-“milky spot” areas of the omentum and peritoneal cavity. “Milky spots” are highly vascularized regions with aggregates of immune cells, capable of innate and adaptive immune functions, and antigen presentation similar to lymph node structures. The involvement of the omentum and adipose tissue suggests the need to develop intraperitoneal immunotherapy similar to the advances seen with intraperitoneal chemotherapy.

39Adipocytes in the omentum produce cytokines and chemokines, including highly secreted IL-6, IL-8, MCP-1, tissue inhibitor of metalloproteinases-1 (TIMP-1) and adiponectin, to promote cancer growth and omental metastases. Adipocytes can alter their lipid metabolism via Fatty acid–binding protein 4 (FAB4) to undergo lipolysis providing fatty acids (FA) to cancer cells as a fuel source for rapid tumor growth. Cancer cells themselves can also alter lipid metabolism, often by upregulating FA receptor CD36 and FAB4 in omental metastases at the tumor/adipocyte interface to promote FA and cholesterol uptake from adipocytes to fuel tumor progression.

40Many studies have suggested an association between obesity and the incidence of ovarian cancer as well as an association with poor prognosis. Indeed, in a murine model of ovarian cancer, metastasis and tumor growth is supported in obese mice through altered regulation of FA pathway and increased immunosuppression, demonstrated by a decreased ratio of M1/M2 macrophages (Figure 2). Improved understanding of how adipocytes and the omentum support ovarian cancer growth and promote peritoneal metastases will reveal therapeutic targets for both conventional therapy and immunotherapy. It will be important to consider how age and obesity may dictate differences in response to immunotherapy and how current models with young, lean mice may fail to accurately model responses to immunotherapy.

7. Conclusions

41In summary, in order to develop better immunotherapies for EOC we need to identify and consider all key elements found in the TME of not only primary tumors but also in ascites and metastases with a focus on how these features affect and are affected by different cancer therapies. It is crucial to take into account the quality of the TME (immune-activating vs. immune-suppressing mechanisms), tumor immunogenicity, tumor burden mutations, tumor stage, patient overall condition, and age, as well as treatment effects on the TME (chemotherapy, neoadjuvant chemotherapy, surgery debulking). Each of these factors may influence the outcome of EOC and the responses to cancer immunotherapies. Moreover, to avoid tumor recurrence, EOC characteristics such as TAA presentation, expression of coinhibitory molecules, production of immunosuppressive cytokines and chemokines should all be considered to find therapeutic combinations that could synergize and achieve maximal benefits to eliminate EOC. Other articles in this special issue will address some of these topics, including the exploration of promising immunotherapies for HGSC that are currently under investigation.

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64.
McGranahan N., Swanton C. Clonal heterogeneity and tumor evolution: Past, present, and the future. Cell. 2017;168:613-628.
Not in our library10.1016/j.cell.2017.01.018
65.
Distinct evolutionary trajectories of primary high‐grade serous ovarian cancers revealed through spatial mutational profiling · 2013
No notice
66.
Caballero O.L., Chen Y.-T. Cancer/testis (CT) antigens: Potential targets for immunotherapy. Cancer Sci. 2009;100:2014-2021.
Not in our library10.1111/j.1349-7006.2009.01303.x
67.
Want M.Y., Lugade A.A., Battaglia S., Odunsi K. Nature of tumor rejection antigens in ovarian cancer. Immunology. 2018.
Not in our library10.1111/imm.12951
68.
Grob J.-J., Mortier L., D’Hondt L., Grange F., Baurain J.F., Dréno B., Lebbe C., Robert C., Dompmartin A., Neyns B., et al. Safety and immunogenicity of MAGE-A3 cancer immunotherapeutic with dacarbazine in patients with MAGE-A3-positive metastatic cutaneous melanoma: An open phase I/II study with a first assessment of a predictive gene signature. ESMO Open. 2017;2:e000203.
Not in our library10.1136/esmoopen-2017-000203
69.
Vansteenkiste J., Zielinski M., Linder A., Dahabreh J., Gonzalez E.E., Malinowski W., Lopez-Brea M., Vanakesa T., Jassem J., Kalofonos H., et al. Adjuvant MAGE-A3 immunotherapy in resected non-small-cell lung cancer: Phase II randomized study results. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2013;31:2396-2403.
Not in our library10.1200/jco.2012.43.7103
70.
Matsuzaki J., Qian F., Luescher I., Lele S., Ritter G., Shrikant P.A., Gnjatic S., Old L.J., Odunsi K. Recognition of naturally processed and ovarian cancer reactive CD8+ T cell epitopes within a promiscuous HLA class II T-helper region of NY-ESO-1. Cancer Immunol. Immunother. CII. 2008;57:1185-1195.
Not in our library10.1007/s00262-008-0450-4
71.
Matsuzaki J., Gnjatic S., Mhawech-Fauceglia P., Beck A., Miller A., Tsuji T., Eppolito C., Qian F., Lele S., Shrikant P., et al. Tumor-infiltrating NY-ESO-1–specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl. Acad. Sci. USA. 2010;107:7875-7880.
Not in our library10.1073/pnas.1003345107
72.
Hanlon D.J., Aldo P.B., Devine L., Alvero A.B., Engberg A.K., Edelson R., Mor G. Enhanced stimulation of anti-ovarian cancer CD8(+) T cells by dendritic cells loaded with nanoparticle encapsulated tumor antigen. Am. J. Reprod. Immunol. 2011;65:597-609.
Not in our library10.1111/j.1600-0897.2010.00968.x
73.
Xue W., Metheringham R.L., Brentville V.A., Gunn B., Symonds P., Yagita H., Ramage J.M., Durrant L.G. SCIB2, an antibody DNA vaccine encoding NY-ESO-1 epitopes, induces potent antitumor immunity which is further enhanced by checkpoint blockade. Oncoimmunology. 2016;5:e1169353.
Not in our library10.1080/2162402x.2016.1169353
74.
Odunsi K., Matsuzaki J., James S.R., Mhawech-Fauceglia P., Tsuji T., Miller A., Zhang W., Akers S.N., Griffiths E.A., Miliotto A., et al. Epigenetic potentiation of NY-ESO-1 vaccine therapy in human ovarian cancer. Cancer Immunol. Res. 2014;2:37-49.
Not in our library10.1158/2326-6066.cir-13-0126
75.
Reid B.M., Permuth J.B., Sellers T.A. Epidemiology of ovarian cancer: A review. Cancer Biol. Med. 2017;14:9-32.
Not in our library10.20892/j.issn.2095-3941.2016.0084
76.
Leffers N., Daemen T., Helfrich W., Boezen H.M., Cohlen B.J., Melief C.J., Nijman H.W. Antigen-specific active immunotherapy for ovarian cancer. The Cochrane Library. 2014.
Not in our library10.1002/14651858.cd007287.pub3
77.
Marincola F.M., Jaffee E.M., Hicklin D.J., Ferrone S. Escape of human solid tumors from T-cell recognition: Molecular mechanisms and functional significance. Adv. Immunol. 2000;74:181-273.
Not in our library10.1016/s0065-2776(08)60911-6
78.
Campoli M., Chang C.-C., Ferrone S. HLA class I antigen loss, tumor immune escape and immune selection. Vaccine. 2002;20(Suppl. 4):40-45.
Not in our library10.1016/s0264-410x(02)00386-9
79.
Chang C.-C., Campoli M., Ferrone S. Classical and nonclassical HLA class I antigen and NK Cell-activating ligand changes in malignant cells: Current challenges and future directions. Adv. Cancer Res. 2005;93:189-234.
Not in our library10.1016/s0065-230x(05)93006-6
80.
Aptsiauri N., Cabrera T., Mendez R., Garcia-Lora A., Ruiz-Cabello F., Garrido F. Role of altered expression of HLA class I molecules in cancer progression. Adv. Exp. Med. Biol. 2007;601:123-131.
Not in our library10.1007/978-0-387-72005-0_13
81.
Han L.Y., Fletcher M.S., Urbauer D.L., Mueller P., Landen C.N., Kamat A.A., Lin Y.G., Merritt W.M., Spannuth W.A., Deavers M.T., et al. HLA class I antigen processing machinery component expression and intratumoral T-Cell infiltrate as independent prognostic markers in ovarian carcinoma. Clin. Cancer Res. 2008;14:3372-3379.
Not in our library10.1158/1078-0432.ccr-07-4433
82.
Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival · 2014
No notice
83.
Matsushita N., Ghazizadeh M., Konishi H., Araki T. Association of ovarian tumor epithelium coexpressing HLA-DR and CA-125 antigens with tumor infiltrating cytotoxic T lymphocytes. J. Nippon Med. Sch. Nippon Ika Daigaku Zasshi. 2003;70:40-44.
Not in our library10.1272/jnms.70.40
84.
Callahan M.J., Nagymanyoki Z., Bonome T., Johnson M.E., Litkouhi B., Sullivan E.H., Hirsch M.S., Matulonis U.A., Liu J., Birrer M.J., et al. Increased HLA-DMB expression in the tumor epithelium is associated with increased CTL infiltration and improved prognosis in advanced-stage serous ovarian cancer. Clin. Cancer Res. 2008;14:7667-7673.
Not in our library10.1158/1078-0432.ccr-08-0479
85.
Garrido F., Perea F., Bernal M., Sánchez-Palencia A., Aptsiauri N., Ruiz-Cabello F. The escape of cancer from T cell-mediated immune surveillance: HLA class I loss and tumor tissue architecture. Vaccines. 2017;5:7.
Not in our library10.3390/vaccines5010007
86.
Garrido F., Ruiz-Cabello F., Aptsiauri N. Rejection versus escape: The tumor MHC dilemma. Cancer Immunol. Immunother. 2017;66:259-271.
Not in our library10.1007/s00262-016-1947-x
87.
Clarke B., Tinker A.V., Lee C.-H., Subramanian S., van de Rijn M., Turbin D., Kalloger S., Han G., Ceballos K., Cadungog M.G., et al. Intraepithelial T cells and prognosis in ovarian carcinoma: Novel associations with stage, tumor type, and BRCA1 loss. Mod. Pathol. 2009;22:393-402.
Not in our library10.1038/modpathol.2008.191
88.
Shah C.A., Allison K.H., Garcia R.L., Gray H.J., Goff B.A., Swisher E.M. Intratumoral T cells, tumor-associated macrophages, and regulatory T cells: Association with p53 mutations, circulating tumor DNA and survival in women with ovarian cancer. Gynecol. Oncol. 2008;109:215-219.
Not in our library10.1016/j.ygyno.2008.01.010
89.
Abiko K., Matsumura N., Hamanishi J., Horikawa N., Murakami R., Yamaguchi K., Yoshioka Y., Baba T., Konishi I., Mandai M. IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br. J. Cancer. 2015;112:1501-1509.
Not in our library10.1038/bjc.2015.101
90.
Hamanishi J., Mandai M., Iwasaki M., Okazaki T., Tanaka Y., Yamaguchi K., Higuchi T., Yagi H., Takakura K., Minato N., et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc. Natl. Acad. Sci. USA. 2007;104:3360-3365.
Not in our library10.1073/pnas.0611533104
91.
Prognostic impact of programmed cell death-1 (PD-1) and PD-ligand 1 (PD-L1) expression in cancer cells and tumor-infiltrating lymphocytes in ovarian high grade serous carcinoma · 2015
No notice
92.
Webb J.R., Milne K., Kroeger D.R., Nelson B.H. PD-L1 expression is associated with tumor-infiltrating T cells and favorable prognosis in high-grade serous ovarian cancer. Gynecol. Oncol. 2016;141:293-302.
Not in our library10.1016/j.ygyno.2016.03.008
93.
Drakes M.L., Mehrotra S., Aldulescu M., Potkul R.K., Liu Y., Grisoli A., Joyce C., O’Brien T.E., Stack M.S., Stiff P.J. Stratification of ovarian tumor pathology by expression of programmed cell death-1 (PD-1) and PD-ligand-1 (PD-L1) in ovarian cancer. J. Ovarian Res. 2018;11.
Not in our library10.1186/s13048-018-0414-z
94.
Goyne H.E., Stone P.J.B., Burnett A.F., Cannon M.J. Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase. J. Immunother. 2014;37:163-169.
Not in our library10.1097/cji.0000000000000030
95.
Hennequart M., Pilotte L., Cane S., Hoffmann D., Stroobant V., Plaen E.D., Eynde B.J.V. den Constitutive IDO1 expression in human tumors is driven by Cyclooxygenase-2 and mediates intrinsic immune resistance. Cancer Immunol. Res. 2017.
Not in our library10.1158/2326-6066.cir-16-0400
96.
Tanizaki Y., Kobayashi A., Toujima S., Shiro M., Mizoguchi M., Mabuchi Y., Yagi S., Minami S., Takikawa O., Ino K. Indoleamine 2,3-dioxygenase promotes peritoneal metastasis of ovarian cancer by inducing an immunosuppressive environment. Cancer Sci. 2014;105:966-973.
Not in our library10.1111/cas.12445
97.
Ino K. Indoleamine 2,3-dioxygenase and immune tolerance in ovarian cancer. Curr. Opin. Obstet. Gynecol. 2011;23:13-18.
Not in our library10.1097/gco.0b013e3283409c79
98.
Inaba T., Ino K., Kajiyama H., Yamamoto E., Shibata K., Nawa A., Nagasaka T., Akimoto H., Takikawa O., Kikkawa F. Role of the immunosuppressive enzyme indoleamine 2,3-dioxygenase in the progression of ovarian carcinoma. Gynecol. Oncol. 2009;115:185-192.
Not in our library10.1016/j.ygyno.2009.07.015
99.
Takao M., Okamoto A., Nikaido T., Urashima M., Takakura S., Saito M., Saito M., Okamoto S., Takikawa O., Sasaki H., et al. Increased synthesis of indoleamine-2,3-dioxygenase protein is positively associated with impaired survival in patients with serous-type, but not with other types of, ovarian cancer. Oncol. Rep. 2007;17:1333-1339.
Not in our library10.3892/or.17.6.1333
100.
Qian F., Villella J., Wallace P.K., Mhawech-Fauceglia P., Tario J.D., Andrews C., Matsuzaki J., Valmori D., Ayyoub M., Frederick P.J., et al. Efficacy of levo-1-methyl tryptophan and dextro-1-methyl tryptophan in reversing indoleamine-2,3-dioxygenase-mediated arrest of T-cell proliferation in human epithelial ovarian cancer. Cancer Res. 2009;69:5498-5504.
Not in our library10.1158/0008-5472.can-08-2106
101.
Sheridan C. IDO inhibitors move center stage in immuno-oncology. Nat. Biotechnol. 2015;33:321-322.
Not in our library10.1038/nbt0415-321
102.
Schreiber R.D., Old L.J., Smyth M.J. Cancer immunoediting: Integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565-1570.
Not in our library10.1126/science.1203486
103.
Okła K., Wertel I., Polak G., Surówka J., Wawruszak A., Kotarski J. Tumor-associated macrophages and myeloid-derived suppressor cells as immunosuppressive mechanism in ovarian cancer patients: Progress and challenges. Int. Rev. Immunol. 2016;35:372-385.
Not in our library10.1080/08830185.2016.1206097
104.
Leffers N., Gooden M.J.M., de Jong R.A., Hoogeboom B.-N., ten Hoor K.A., Hollema H., Boezen H.M., van der Zee A.G.J., Daemen T., Nijman H.W. Prognostic significance of tumor-infiltrating T-lymphocytes in primary and metastatic lesions of advanced stage ovarian cancer. Cancer Immunol. Immunother. CII. 2009;58:449-459.
Not in our library10.1007/s00262-008-0583-5
105.
Raspollini M.R., Castiglione F., Rossi Degl’innocenti D., Amunni G., Villanucci A., Garbini F., Baroni G., Taddei G.L. Tumour-infiltrating gamma/delta T-lymphocytes are correlated with a brief disease-free interval in advanced ovarian serous carcinoma. Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2005;16:590-596.
Not in our library10.1093/annonc/mdi112
106.
Sato E., Olson S.H., Ahn J., Bundy B., Nishikawa H., Qian F., Jungbluth A.A., Frosina D., Gnjatic S., Ambrosone C., et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl. Acad. Sci. USA. 2005;102:18538-18543.
Not in our library10.1073/pnas.0509182102
107.
Tomsová M., Melichar B., Sedláková I., Steiner I. Prognostic significance of CD3+ tumor-infiltrating lymphocytes in ovarian carcinoma. Gynecol. Oncol. 2008;108:415-420.
Not in our library10.1016/j.ygyno.2007.10.016
108.
Nielsen J.S., Sahota R.A., Milne K., Kost S.E., Nesslinger N.J., Watson P.H., Nelson B.H. CD20+ tumor-infiltrating lymphocytes have an atypical CD27- memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin. Cancer Res. 2012;18:3281-3292.
Not in our library10.1158/1078-0432.ccr-12-0234
109.
Barnett J.C., Bean S.M., Whitaker R.S., Kondoh E., Baba T., Fujii S., Marks J.R., Dressman H.K., Murphy S.K., Berchuck A. Ovarian cancer tumor infiltrating T-regulatory (T(reg)) cells are associated with a metastatic phenotype. Gynecol. Oncol. 2010;116:556-562.
Not in our library10.1016/j.ygyno.2009.11.020
110.
Hamanishi J., Mandai M., Abiko K., Matsumura N., Baba T., Yoshioka Y., Kosaka K., Konishi I. The comprehensive assessment of local immune status of ovarian cancer by the clustering of multiple immune factors. Clin. Immunol. 2011;141:338-347.
Not in our library10.1016/j.clim.2011.08.013
111.
Hwang W.-T., Adams S.F., Tahirovic E., Hagemann I.S., Coukos G. Prognostic significance of tumor-infiltrating T cells in ovarian cancer: A meta-analysis. Gynecol. Oncol. 2012;124:192-198.
Not in our library10.1016/j.ygyno.2011.09.039
112.
Dadmarz R.D., Ordoubadi A., Mixon A., Thompson C.O., Barracchini K.C., Hijazi Y.M., Steller M.A., Rosenberg S.A., Schwartzentruber D.J. Tumor-infiltrating lymphocytes from human ovarian cancer patients recognize autologous tumor in an MHC class II-restricted fashion. Cancer J. Sci. Am. 1996;2:263-272.
Not in our library
113.
Bronger H., Singer J., Windmüller C., Reuning U., Zech D., Delbridge C., Dorn J., Kiechle M., Schmalfeldt B., Schmitt M., et al. CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br. J. Cancer. 2016;115:553-563.
Not in our library10.1038/bjc.2016.172
114.
Liu M., Matsumura N., Mandai M., Li K., Yagi H., Baba T., Suzuki A., Hamanishi J., Fukuhara K., Konishi I. Classification using hierarchical clustering of tumor-infiltrating immune cells identifies poor prognostic ovarian cancers with high levels of COX expression. Mod. Pathol. 2009;22:373-384.
Not in our library10.1038/modpathol.2008.187
115.
Hermans C., Anz D., Engel J., Kirchner T., Endres S., Mayr D. Analysis of FoxP3+ T-regulatory cells and CD8+ T-cells in ovarian carcinoma: Location and tumor infiltration patterns are key prognostic markers. PLoS ONE. 2014;9:e111757.
Not in our library10.1371/journal.pone.0111757
116.
Shi J.-X., Qin J.-J., Ye H., Wang P., Wang K.-J., Zhang J.-Y. Tumor associated antigens or anti-TAA autoantibodies as biomarkers in the diagnosis of ovarian cancer: A systematic review with meta-analysis. Expert Rev. Mol. Diagn. 2015;15:829-852.
Not in our library10.1586/14737159.2015.1035713
117.
Taylor D.D., Gercel-Taylor C., Parker L.P. Patient-derived tumor-reactive antibodies as diagnostic markers for ovarian cancer. Gynecol. Oncol. 2009;115:112-120.
Not in our library10.1016/j.ygyno.2009.06.031
118.
Taylor D.D., Atay S., Metzinger D.S., Gercel-Taylor C. Characterization of humoral responses of ovarian cancer patients: Antibody subclasses and antigenic components. Gynecol. Oncol. 2010;116:213-221.
Not in our library10.1016/j.ygyno.2009.11.005
119.
Jang M., Yew P.-Y., Hasegawa K., Ikeda Y., Fujiwara K., Fleming G.F., Nakamura Y., Park J.-H. Characterization of T cell repertoire of blood, tumor, and ascites in ovarian cancer patients using next generation sequencing. Oncoimmunology. 2015;4:e1030561.
Not in our library10.1080/2162402x.2015.1030561
120.
Landskron J., Helland Ø., Torgersen K.M., Aandahl E.M., Gjertsen B.T., Bjørge L., Taskén K. Activated regulatory and memory T-cells accumulate in malignant ascites from ovarian carcinoma patients. Cancer Immunol. Immunother. 2015;64:337-347.
Not in our library10.1007/s00262-014-1636-6
121.
Lukesova S., Vroblova V., Tosner J., Kopecky J., Sedlakova I., Čermáková E., Vokurkova D., Kopecky O. Comparative study of various subpopulations of cytotoxic cells in blood and ascites from patients with ovarian carcinoma. Contemp. Oncol. Poznan Pol. 2015;19:290-299.
Not in our library10.5114/wo.2015.54388
122.
A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer · 2018
Not checked
123.
Nelson B.H. The impact of T-cell immunity on ovarian cancer outcomes. Immunol. Rev. 2008;222:101-116.
Not in our library10.1111/j.1600-065x.2008.00614.x
124.
Tsiatas M.L., Gyftaki R., Liacos C., Politi E., Rodolakis A., Dimopoulos M.-A., Bamias A. Study of T lymphocytes infiltrating peritoneal metastases in advanced ovarian cancer: Associations with vascular endothelial growth factor levels and prognosis in patients receiving platinum-based chemotherapy. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 2009;19:1329-1334.
Not in our library10.1111/igc.0b013e3181b7a40e
125.
Le Page C., Marineau A., Bonza P.K., Rahimi K., Cyr L., Labouba I., Madore J., Delvoye N., Mes-Masson A.-M., Provencher D.M., et al. BTN3A2 expression in epithelial ovarian cancer is associated with higher tumor infiltrating T cells and a better prognosis. PLoS ONE. 2012;7:e38541.
Not in our library10.1371/journal.pone.0038541
126.
Nesbeth Y.C., Martinez D.G., Toraya S., Scarlett U.K., Cubillos-Ruiz J.R., Rutkowski M.R., Conejo-Garcia J.R. CD4+ T cells elicit host immune responses to MHC class II-negative ovarian cancer through CCL5 secretion and CD40-mediated licensing of dendritic cells. J. Immunol. 2010;184:5654-5662.
Not in our library10.4049/jimmunol.0903247
127.
Hanahan D., Coussens L.M. Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309-322.
Not in our library10.1016/j.ccr.2012.02.022
128.
Mittal D., Gubin M.M., Schreiber R.D., Smyth M.J. New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr. Opin. Immunol. 2014;27:16-25.
Not in our library10.1016/j.coi.2014.01.004
129.
Sehouli J., Loddenkemper C., Cornu T., Schwachula T., Hoffmüller U., Grützkau A., Lohneis P., Dickhaus T., Gröne J., Kruschewski M., et al. Epigenetic quantification of tumor-infiltrating T-lymphocytes. Epigenetics. 2011;6:236-246.
Not in our library10.4161/epi.6.2.13755
130.
Curiel T.J., Coukos G., Zou L., Alvarez X., Cheng P., Mottram P., Evdemon-Hogan M., Conejo-Garcia J.R., Zhang L., Burow M., et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat. Med. 2004;10:942-949.
Not in our library10.1038/nm1093
131.
Woo E.Y., Chu C.S., Goletz T.J., Schlienger K., Yeh H., Coukos G., Rubin S.C., Kaiser L.R., June C.H. Regulatory CD4(+)CD25(+) T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 2001;61:4766-4772.
Not in our library
132.
Kryczek I., Liu R., Wang G., Wu K., Shu X., Szeliga W., Vatan L., Finlayson E., Huang E., Simeone D., et al. FOXP3 defines regulatory T cells in human tumor and autoimmune disease. Cancer Res. 2009;69:3995-4000.
Not in our library10.1158/0008-5472.can-08-3804
133.
Napoletano C., Bellati F., Landi R., Pauselli S., Marchetti C., Visconti V., Sale P., Liberati M., Rughetti A., Frati L., et al. Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression. J. Cell. Mol. Med. 2010;14:2748-2759.
Not in our library10.1111/j.1582-4934.2009.00911.x
134.
Fialová A., Partlová S., Sojka L., Hromádková H., Brtnický T., Fučíková J., Kocián P., Rob L., Bartůňková J., Spíšek R. Dynamics of T-cell infiltration during the course of ovarian cancer: The gradual shift from a Th17 effector cell response to a predominant infiltration by regulatory T-cells. Int. J. Cancer. 2013;132:1070-1079.
Not in our library10.1002/ijc.27759
135.
Facciabene A., Peng X., Hagemann I.S., Balint K., Barchetti A., Wang L.-P., Gimotty P.A., Gilks C.B., Lal P., Zhang L., et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature. 2011;475:226-230.
Not in our library10.1038/nature10169
136.
Kryczek I., Wei S., Zhu G., Myers L., Mottram P., Cheng P., Chen L., Coukos G., Zou W. Relationship between B7-H4, regulatory T cells, and patient outcome in human ovarian carcinoma. Cancer Res. 2007;67:8900-8905.
Not in our library10.1158/0008-5472.can-07-1866
137.
Redjimi N., Raffin C., Raimbaud I., Pignon P., Matsuzaki J., Odunsi K., Valmori D., Ayyoub M. CXCR3+ T regulatory cells selectively accumulate in human ovarian carcinomas to limit type I immunity. Cancer Res. 2012;72:4351-4360.
Not in our library10.1158/0008-5472.can-12-0579
138.
Giuntoli R.L., Webb T.J., Zoso A., Rogers O., Diaz-Montes T.P., Bristow R.E., Oelke M. Ovarian Cancer-associated Ascites Demonstrates Altered Immune Environment: Implications for Antitumor Immunity. Anticancer Res. 2009;29:2875-2884.
Not in our library
139.
Wolf D., Wolf A.M., Rumpold H., Fiegl H., Zeimet A.G., Muller-Holzner E., Deibl M., Gastl G., Gunsilius E., Marth C. The expression of the regulatory T cell-specific forkhead box transcription factor FoxP3 is associated with poor prognosis in ovarian cancer. Clin. Cancer Res. 2005;11:8326-8331.
Not in our library10.1158/1078-0432.ccr-05-1244
140.
Mhawech-Fauceglia P., Wang D., Ali L., Lele S., Huba M.A., Liu S., Odunsi K. Intraepithelial T cells and tumor-associated macrophages in ovarian cancer patients. Cancer Immun. 2013;13:1.
Not in our library
141.
Systematic Analysis of Immune Infiltrates in High-Grade Serous Ovarian Cancer Reveals CD20, FoxP3 and TIA-1 as Positive Prognostic Factors · 2009
Corrected
142.
Wu M., Chen X., Lou J., Zhang S., Zhang X., Huang L., Sun R., Huang P., Wang F., Pan S. TGF-β1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment. Oncotarget. 2016;7:44534-44544.
Not in our library10.18632/oncotarget.10003
143.
Zhang S., Ke X., Zeng S., Wu M., Lou J., Wu L., Huang P., Huang L., Wang F., Pan S. Analysis of CD8+ Treg cells in patients with ovarian cancer: A possible mechanism for immune impairment. Cell. Mol. Immunol. 2015;12:580-591.
Not in our library10.1038/cmi.2015.57
144.
Wang R.-F. CD8+ regulatory T cells, their suppressive mechanisms, and regulation in cancer. Hum. Immunol. 2008;69:811-814.
Not in our library10.1016/j.humimm.2008.08.276
145.
Yigit R., Massuger L.F.A.G., Figdor C.G., Torensma R. Ovarian cancer creates a suppressive microenvironment to escape immune elimination. Gynecol. Oncol. 2010;117:366-372.
Not in our library10.1016/j.ygyno.2010.01.019
146.
Sarvaria A., Madrigal J.A., Saudemont A. B cell regulation in cancer and anti-tumor immunity. Cell. Mol. Immunol. 2017;14:662-674.
Not in our library10.1038/cmi.2017.35
147.
Montfort A., Pearce O., Maniati E., Vincent B.G., Bixby L., Böhm S., Dowe T., Wilkes E.H., Chakravarty P., Thompson R., et al. A strong B-cell response is part of the immune landscape in human high-grade serous ovarian metastases. Clin. Cancer Res. 2017;23:250-262.
Not in our library10.1158/1078-0432.ccr-16-0081
148.
Rosser E.C., Mauri C. Regulatory B cells: Origin, phenotype, and function. Immunity. 2015;42:607-612.
Not in our library10.1016/j.immuni.2015.04.005
149.
Lundgren S., Berntsson J., Nodin B., Micke P., Jirström K. Prognostic impact of tumour-associated B cells and plasma cells in epithelial ovarian cancer. J. Ovarian Res. 2016;9:21.
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150.
Yang C., Lee H., Jove V., Deng J., Zhang W., Liu X., Forman S., Dellinger T.H., Wakabayashi M., Yu H., et al. Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS ONE. 2013;8:e54029.
Not in our library10.1371/journal.pone.0054029
151.
Dong H.P., Elstrand M.B., Holth A., Silins I., Berner A., Trope C.G., Davidson B., Risberg B. NK- and B-cell infiltration correlates with worse outcome in metastatic ovarian carcinoma. Am. J. Clin. Pathol. 2006;125:451-458.
Not in our library10.1309/15b66dqmfyym78cj
152.
Lu P.H., Negrin R.S. A novel population of expanded human CD3+CD56+ cells derived from T cells with potent in vivo antitumor activity in mice with severe combined immunodeficiency. J. Immunol. 1994;153:1687-1696.
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153.
Schmidt-Wolf I.G., Lefterova P., Mehta B.A., Fernandez L.P., Huhn D., Blume K.G., Weissman I.L., Negrin R.S. Phenotypic characterization and identification of effector cells involved in tumor cell recognition of cytokine-induced killer cells. Exp. Hematol. 1993;21:1673-1679.
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154.
Bamias A., Tsiatas M.L., Kafantari E., Liakou C., Rodolakis A., Voulgaris Z., Vlahos G., Papageorgiou T., Tsitsilonis O., Bamia C., et al. Significant differences of lymphocytes isolated from ascites of patients with ovarian cancer compared to blood and tumor lymphocytes. Association of CD3+CD56+ cells with platinum resistance. Gynecol. Oncol. 2007;106:75-81.
Not in our library10.1016/j.ygyno.2007.02.029
155.
Bamias A., Koutsoukou V., Terpos E., Tsiatas M.L., Liakos C., Tsitsilonis O., Rodolakis A., Voulgaris Z., Vlahos G., Papageorgiou T., et al. Correlation of NK T-like CD3+CD56+ cells and CD4+CD25+(hi) regulatory T cells with VEGF and TNFalpha in ascites from advanced ovarian cancer: Association with platinum resistance and prognosis in patients receiving first-line, platinum-based chemotherapy. Gynecol. Oncol. 2008;108:421-427.
Not in our library10.1016/j.ygyno.2007.10.018
156.
Novel Approaches to Exploiting Invariant NKT Cells in Cancer Immunotherapy · 2018
No notice
157.
Guillerey C., Huntington N.D., Smyth M.J. Targeting natural killer cells in cancer immunotherapy. Nat. Immunol. 2016;17:1025-1036.
Not in our library10.1038/ni.3518
158.
Sungur C.M., Murphy W.J. Positive and negative regulation by NK cells in cancer. Crit. Rev. Oncog. 2014;19:57-66.
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159.
Voskoboinik I., Smyth M.J., Trapani J.A. Perforin-mediated target-cell death and immune homeostasis. Nat. Rev. Immunol. 2006;6:940-952.
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160.
Lai P., Rabinowich H., Crowley-Nowick P.A., Bell M.C., Mantovani G., Whiteside T.L. Alterations in expression and function of signal-transducing proteins in tumor-associated T and natural killer cells in patients with ovarian carcinoma. Clin. Cancer Res. 1996;2:161-173.
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161.
Yunusova N.V., Stakheyeva M.N., Molchanov S.V., Afanas’ev S.G., Tsydenova A.A., Kolomiets L.A., Cherdyntseva N.V. Functional activity of natural killer cells in biological fluids in patients with colorectal and ovarian cancers. Cent.-Eur. J. Immunol. 2018;43:26-32.
Not in our library10.5114/ceji.2018.74870
162.
Webb J.R., Milne K., Watson P., Deleeuw R.J., Nelson B.H. Tumor-infiltrating lymphocytes expressing the tissue resident memory marker CD103 are associated with increased survival in high-grade serous ovarian cancer. Clin. Cancer Res. 2014;20:434-444.
Not in our library10.1158/1078-0432.ccr-13-1877
163.
Garzetti G.G., Cignitti M., Ciavattini A., Fabris N., Romanini C. Natural killer cell activity and progression-free survival in ovarian cancer. Gynecol. Obstet. Invest. 1993;35:118-120.
Not in our library10.1159/000292678
164.
Li K., Mandai M., Hamanishi J., Matsumura N., Suzuki A., Yagi H., Yamaguchi K., Baba T., Fujii S., Konishi I. Clinical significance of the NKG2D ligands, MICA/B and ULBP2 in ovarian cancer: High expression of ULBP2 is an indicator of poor prognosis. Cancer Immunol. Immunother. CII. 2009;58:641-652.
Not in our library10.1007/s00262-008-0585-3
165.
Tumor-Associated Macrophages Contribute to Tumor Progression in Ovarian Cancer · 2014
No notice
166.
Takaishi K., Komohara Y., Tashiro H., Ohtake H., Nakagawa T., Katabuchi H., Takeya M. Involvement of M2-polarized macrophages in the ascites from advanced epithelial ovarian carcinoma in tumor progression via Stat3 activation. Cancer Sci. 2010;101:2128-2136.
Not in our library10.1111/j.1349-7006.2010.01652.x
167.
Kawamura K., Komohara Y., Takaishi K., Katabuchi H., Takeya M. Detection of M2 macrophages and colony-stimulating factor 1 expression in serous and mucinous ovarian epithelial tumors. Pathol. Int. 2009;59:300-305.
Not in our library10.1111/j.1440-1827.2009.02369.x
168.
Hagemann T., Wilson J., Burke F., Kulbe H., Li N.F., Plüddemann A., Charles K., Gordon S., Balkwill F.R. Ovarian cancer cells polarize macrophages toward a tumor-associated phenotype. J. Immunol. 2006;176:5023-5032.
Not in our library10.4049/jimmunol.176.8.5023
169.
Sica G.L., Choi I.H., Zhu G., Tamada K., Wang S.D., Tamura H., Chapoval A.I., Flies D.B., Bajorath J., Chen L. B7-H4, a molecule of the B7 family, negatively regulates T cell immunity. Immunity. 2003;18:849-861.
Not in our library10.1016/s1074-7613(03)00152-3
170.
Yuan X., Zhang J., Li D., Mao Y., Mo F., Du W., Ma X. Prognostic significance of tumor-associated macrophages in ovarian cancer: A meta-analysis. Gynecol. Oncol. 2017;147:181-187.
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171.
Lan C., Huang X., Lin S., Huang H., Cai Q., Wan T., Lu J., Liu J. Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer. Technol. Cancer Res. Treat. 2013;12:259-267.
Not in our library10.7785/tcrt.2012.500312
172.
He Y., Zhang M., Wu X., Sun X., Xu T., He Q., Di W. High MUC2 expression in ovarian cancer is inversely associated with the M1/M2 ratio of tumor-associated macrophages and patient survival time. PLoS ONE. 2013;8:e79769.
Not in our library10.1371/journal.pone.0079769
173.
A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients · 2014
No notice
174.
No J.H., Moon J.M., Kim K., Kim Y.-B. Prognostic significance of serum soluble CD163 level in patients with epithelial ovarian cancer. Gynecol. Obstet. Investig. 2013;75:263-267.
Not in our library10.1159/000349892
175.
Gordon I.O., Freedman R.S. Defective antitumor function of monocyte-derived macrophages from epithelial ovarian cancer patients. Clin. Cancer Res. 2006;12:1515-1524.
Not in our library10.1158/1078-0432.ccr-05-2254
176.
Reprogramming of Tumor-Associated Macrophages with Anticancer Therapies: Radiotherapy versus Chemo- and Immunotherapies · 2017
No notice
177.
Youn J.-I., Gabrilovich D.I. The biology of myeloid-derived suppressor cells: The blessing and the curse of morphological and functional heterogeneity. Eur. J. Immunol. 2010;40:2969-2975.
Not in our library10.1002/eji.201040895
178.
Gabrilovich D.I., Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 2009;9:162-174.
Not in our library10.1038/nri2506
179.
Obermajer N., Muthuswamy R., Odunsi K., Edwards R.P., Kalinski P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 2011;71:7463-7470.
Not in our library10.1158/0008-5472.can-11-2449
180.
Cui T.X., Kryczek I., Zhao L., Zhao E., Kuick R., Roh M.H., Vatan L., Szeliga W., Mao Y., Thomas D.G., et al. Myeloid-derived suppressor cells enhance stemness of cancer cells by inducing microRNA101 and suppressing the corepressor CtBP2. Immunity. 2013;39:611-621.
Not in our library10.1016/j.immuni.2013.08.025
181.
Wu L., Deng Z., Peng Y., Han L., Liu J., Wang L., Li B., Zhao J., Jiao S., Wei H. Ascites-derived IL-6 and IL-10 synergistically expand CD14+HLA-DR-/low myeloid-derived suppressor cells in ovarian cancer patients. Oncotarget. 2017;8:76843-76856.
Not in our library10.18632/oncotarget.20164
182.
Horikawa N., Abiko K., Matsumura N., Hamanishi J., Baba T., Yamaguchi K., Yoshioka Y., Koshiyama M., Konishi I. Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells. Clin. Cancer Res. 2017;23:587-599.
Not in our library10.1158/1078-0432.ccr-16-0387
183.
Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation · 2018
No notice
184.
Adenosine-generating ovarian cancer cells attract myeloid cells which differentiate into adenosine-generating tumor associated macrophages – a self-amplifying, CD39- and CD73-dependent mechanism for tumor immune escape · 2016
No notice
185.
Li L., Wang L., Li J., Fan Z., Yang L., Zhang Z., Zhang C., Yue D., Qin G., Zhang T., et al. Metformin-induced reduction of CD39 and CD73 blocks myeloid-derived suppressor cell activity in patients with ovarian cancer. Cancer Res. 2018;78:1779-1791.
Not in our library10.1158/0008-5472.can-17-2460
186.
Cheng L., Wu S., Zhang K., Qing Y., Xu T. A comprehensive overview of exosomes in ovarian cancer: Emerging biomarkers and therapeutic strategies. J. Ovarian Res. 2017;10:73.
Not in our library10.1186/s13048-017-0368-6
187.
TGFβ1 in fibroblasts-derived exosomes promotes epithelial-mesenchymal transition of ovarian cancer cells · 2017
No notice
188.
Exosomal transfer of stroma-derived miR21 confers paclitaxel resistance in ovarian cancer cells through targeting APAF1 · 2016
No notice
189.
Peng P., Yan Y., Keng S. Exosomes in the ascites of ovarian cancer patients: Origin and effects on anti-tumor immunity. Oncol. Rep. 2011;25:749-762.
Not in our library10.3892/or.2010.1119
190.
Keerthikumar S., Chisanga D., Ariyaratne D., Al Saffar H., Anand S., Zhao K., Samuel M., Pathan M., Jois M., Chilamkurti N., et al. ExoCarta: A web-based compendium of exosomal cargo. J. Mol. Biol. 2016;428:688-692.
Not in our library10.1016/j.jmb.2015.09.019
191.
Mathivanan S., Simpson R.J. ExoCarta: A compendium of exosomal proteins and RNA. Proteomics. 2009;9:4997-5000.
Not in our library10.1002/pmic.200900351
192.
Keller S., König A.-K., Marmé F., Runz S., Wolterink S., Koensgen D., Mustea A., Sehouli J., Altevogt P. Systemic presence and tumor-growth promoting effect of ovarian carcinoma released exosomes. Cancer Lett. 2009;278:73-81.
Not in our library10.1016/j.canlet.2008.12.028
193.
Valenti R., Huber V., Iero M., Filipazzi P., Parmiani G., Rivoltini L. Tumor-released microvesicles as vehicles of immunosuppression. Cancer Res. 2007;67:2912-2915.
Not in our library10.1158/0008-5472.can-07-0520
194.
Robbins P.D., Morelli A.E. Regulation of immune responses by extracellular vesicles. Nat. Rev. Immunol. 2014;14:195-208.
Not in our library10.1038/nri3622
195.
Cai X., Caballero-Benitez A., Gewe M.M., Jenkins I.C., Drescher C.W., Strong R.K., Spies T., Groh V. Control of tumor initiation by NKG2D naturally expressed on ovarian cancer cells. Neoplasia. 2017;19:471-482.
Not in our library10.1016/j.neo.2017.03.005
196.
Syn N.L., Wang L., Chow E.K.-H., Lim C.T., Goh B.-C. Exosomes in cancer nanomedicine and immunotherapy: Prospects and challenges. Trends Biotechnol. 2017;35:665-676.
Not in our library10.1016/j.tibtech.2017.03.004
197.
Labiche A., Heutte N., Herlin P., Chasle J., Gauduchon P., Elie N. Stromal compartment as a survival prognostic factor in advanced ovarian carcinoma. Int. J. Gynecol. Cancer Off. J. Int. Gynecol. Cancer Soc. 2010;20:28-33.
Not in our library10.1111/igc.0b013e3181bda1cb
198.
Deying W., Feng G., Shumei L., Hui Z., Ming L., Hongqing W. CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells. Biosci. Rep. 2017;37.
Not in our library10.1042/bsr20160470
199.
Kwon Y., Smith B.D., Zhou Y., Kaufman M.D., Godwin A.K. Effective inhibition of c-MET-mediated signaling, growth and migration of ovarian cancer cells is influenced by the ovarian tissue microenvironment. Oncogene. 2015;34:144-153.
Not in our library10.1038/onc.2013.539
200.
Erez N., Glanz S., Raz Y., Avivi C., Barshack I. Cancer associated fibroblasts express pro-inflammatory factors in human breast and ovarian tumors. Biochem. Biophys. Res. Commun. 2013;437:397-402.
Not in our library10.1016/j.bbrc.2013.06.089
201.
Zhou B., Sun C., Li N., Shan W., Lu H., Guo L., Guo E., Xia M., Weng D., Meng L., et al. Cisplatin-induced CCL5 secretion from CAFs promotes cisplatin-resistance in ovarian cancer via regulation of the STAT3 and PI3K/Akt signaling pathways. Int. J. Oncol. 2016;48:2087-2097.
Not in our library10.3892/ijo.2016.3442
202.
Lau T.-S., Chung T.K.-H., Cheung T.-H., Chan L.K.-Y., Cheung L.W.-H., Yim S.-F., Siu N.S.-S., Lo K.-W., Yu M.M.-Y., Kulbe H., et al. Cancer cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts. J. Pathol. 2014;232:43-56.
Not in our library10.1002/path.4258
203.
Wang L., Zhang F., Cui J.-Y., Chen L., Chen Y.-T., Liu B.-W. CAFs enhance paclitaxel resistance by inducing EMT through the IL-6/JAK2/STAT3 pathway. Oncol. Rep. 2018;39:2081-2090.
Not in our library10.3892/or.2018.6311
204.
miR200-regulated CXCL12β promotes fibroblast heterogeneity and immunosuppression in ovarian cancers · 2018
No notice
205.
Schauer I.G., Zhang J., Xing Z., Guo X., Mercado-Uribe I., Sood A.K., Huang P., Liu J. Interleukin-1β promotes ovarian tumorigenesis through a p53/NF-κB-mediated inflammatory response in stromal fibroblasts. Neoplasia. 2013;15:409-420.
Not in our library10.1593/neo.121228
206.
Yeung T.-L., Leung C.S., Wong K.-K., Samimi G., Thompson M.S., Liu J., Zaid T.M., Ghosh S., Birrer M.J., Mok S.C. TGF-β modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment. Cancer Res. 2013;73:5016-5028.
Not in our library10.1158/0008-5472.can-13-0023
207.
Giusti I., Francesco M.D., Ascenzo S.D., Palmerini M.G., Macchiarelli G., Carta G., Dolo V. Ovarian cancer-derived extracellular vesicles affect normal human fibroblast behavior. Cancer Biol. Ther. 2018;1-44.
Not in our library10.1080/15384047.2018.1451286
208.
Wei R., Lv M., Li F., Cheng T., Zhang Z., Jiang G., Zhou Y., Gao R., Wei X., Lou J., et al. Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis. Oncotarget. 2017;8:67315-67328.
Not in our library10.18632/oncotarget.18621
209.
Leung C.S., Yeung T.-L., Yip K.-P., Wong K.-K., Ho S.Y., Mangala L.S., Sood A.K., Lopez-Berestein G., Sheng J., Wong S.T., et al. Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance. J. Clin. Investig. 2018;128:589-606.
Not in our library10.1172/jci95200
210.
Lengyel E. Ovarian Cancer Development and Metastasis. Am. J. Pathol. 2010;177:1053-1064.
Not in our library10.2353/ajpath.2010.100105
211.
Lengyel E., Makowski L., DiGiovanni J., Kolonin M.G. Cancer as a matter of fat: The crosstalk between adipose tissue and tumors. Trends Cancer. 2018;4:374-384.
Not in our library10.1016/j.trecan.2018.03.004
212.
Meza-Perez S., Randall T.D. Immunological functions of the omentum. Trends Immunol. 2017;38:526-536.
Not in our library10.1016/j.it.2017.03.002
213.
Clark R., Krishnan V., Schoof M., Rodriguez I., Theriault B., Chekmareva M., Rinker-Schaeffer C. Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models. Am. J. Pathol. 2013;183:576-591.
Not in our library10.1016/j.ajpath.2013.04.023
214.
Gerber S.A., Rybalko V.Y., Bigelow C.E., Lugade A.A., Foster T.H., Frelinger J.G., Lord E.M. Preferential attachment of peritoneal tumor metastases to omental immune aggregates and possible role of a unique vascular microenvironment in metastatic survival and growth. Am. J. Pathol. 2006;169:1739-1752.
Not in our library10.2353/ajpath.2006.051222
215.
Krishnan V., Clark R., Chekmareva M., Johnson A., George S., Shaw P., Seewaldt V., Rinker-Schaeffer C. In vivo and Ex vivo approaches to study ovarian cancer metastatic colonization of milky spot structures in peritoneal adipose. J. Vis. Exp. JoVE. 2015.
Not in our library10.3791/52721
216.
Nieman K.M., Kenny H.A., Penicka C.V., Ladanyi A., Buell-Gutbrod R., Zillhardt M.R., Romero I.L., Carey M.S., Mills G.B., Hotamisligil G.S., et al. Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat. Med. 2011;17:1498-1503.
Not in our library10.1038/nm.2492
217.
Oosterling S.J., van der Bij G.J., Bögels M., van der Sijp J.R.M., Beelen R.H.J., Meijer S., van Egmond M. Insufficient ability of omental milky spots to prevent peritoneal tumor outgrowth supports omentectomy in minimal residual disease. Cancer Immunol. Immunother. 2006;55:1043-1051.
Not in our library10.1007/s00262-005-0101-y
218.
Ladanyi A., Mukherjee A., Kenny H.A., Johnson A., Mitra A.K., Sundaresan S., Nieman K.M., Pascual G., Benitah S.A., Montag A., et al. Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene. 2018;37:2285-2301.
Not in our library10.1038/s41388-017-0093-z
219.
Protani M.M., Nagle C.M., Webb P.M. Obesity and ovarian cancer survival: A systematic review and meta-analysis. Cancer Prev. Res. 2012;5:901-910.
Not in our library10.1158/1940-6207.capr-12-0048
220.
Liu Y., Metzinger M.N., Lewellen K.A., Cripps S.N., Carey K.D., Harper E.I., Shi Z., Tarwater L., Grisoli A., Lee E., et al. Obesity contributes to ovarian cancer metastatic success through increased lipogenesis, enhanced vascularity, and decreased infiltration of M1 macrophages. Cancer Res. 2015;75:5046-5057.
Not in our library10.1158/0008-5472.can-15-0706
221.
James B.R., Tomanek-Chalkley A., Askeland E.J., Kucaba T., Griffith T.S., Norian L.A. Diet-induced obesity alters dendritic cell function in the presence and absence of tumor growth. J. Immunol. 2012;189:1311-1321.
Not in our library10.4049/jimmunol.1100587
222.
Macia L., Delacre M., Abboud G., Ouk T.-S., Delanoye A., Verwaerde C., Saule P., Wolowczuk I. Impairment of dendritic cell functionality and steady-state number in obese mice. J. Immunol. 2006;177:5997-6006.
Not in our library10.4049/jimmunol.177.9.5997
223.
Shirakawa K., Yan X., Shinmura K., Endo J., Kataoka M., Katsumata Y., Yamamoto T., Anzai A., Isobe S., Yoshida N., et al. Obesity accelerates T cell senescence in murine visceral adipose tissue. J. Clin. Investig. 2016;126:4626-4639.
Not in our library10.1172/jci88606
224.
McCloskey C.W., Rodriguez G.M., Galpin K.J.C., Vanderhyden B.C. Ovarian cancer immunotherapy: Preclinical models and emerging therapeutics. Cancers. 2018.
Not in our library10.3390/cancers10080244

Cited by papers we hold 3

Extracellular vesicles in ovarian cancer chemoresistance, metastasis, and immune evasion · 2022
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Immunotherapy for Ovarian Cancer: Adjuvant, Combination, and Neoadjuvant · 2020
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Ovarian cancer: Current status and strategies for improving therapeutic outcomes · 2019
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