Immune Response In Ovarian Cancer Research Articles

Therapeutic targeting of the immunosuppressive axis in ovarian cancer using dietary supplements

Abstract Ovarian cancer is the deadliest gynecologic malignancy worldwide and mortality rates have remained steady despite advances in treatment. A major obstacle for current therapies is overcoming tumor immunosuppression, therefore targeting inhibitory factors produced in the tumor microenvironment could enhance antitumor responses. Natural Killer T (NKT) cells, a subset of T cells that recognize glycolipid antigens presented by CD1d, are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which binds with high affinity to CD1d, thereby suppressing NKT cell activation. In addition to GD3, we have identified vascular endothelial growth factor (VEGF) as another immunosuppressive factor secreted by ovarian cancers. We found that VEGF inhibition results in decreased GD3 expression in human ovarian cancer cell lines and restoration of NKT cell responses. In addition, we found that treatment with VEGF can directly impair NKT cell functional responses. To therapeutically target the VEGF-GD3 signaling cascade, mouse and human ovarian cancer cell lines were treated with triptolide, a phytochemical which has demonstrated potent antitumor activity in vitro and in vivo. Treatment with triptolide reduces VEGF secretion by ovarian cancer cell lines and results in a concomitant decrease in the expression of GD3 synthase. In addition, pre-treatment of ovarian cancer cells with triptolide improves the ability of NKT cells to recognize and lyse the cancer cells. Thus, we have identified a novel therapeutic strategy that can be used to block the production of immunosuppressive factors, thereby restoring NKT cell-mediated antitumor immune responses in ovarian cancer.

Interactions of ficolin-3 with ovarian cancer cells

BackgroundFicolin-3 is a pattern-recognition molecule with the ability to activate the lectin pathway of complement. It is found in lung, liver and blood, but its physiological role is unclear. We have investigated interaction of recombinant ficolin-3 with malignant cells and tissues. Material and MethodsCells of various lines of human origin as well as ovarian tissue sections have been studied with the use of flow cytometry and immunohistochemistry. ResultsRecombinant (but not serum-derived) ficolin-3 was found to bind strongly to the ovarian cancer cell lines, SKOV-3, OVCAR-3 and ES-2, at concentrations of 2.5 μg/ml and above. Moreover, His-tagged recombinant ficolin-3 (10 μg/ml) preferentially stained ovarian tissue sections from patients with malignant tumours compared with those from patients without. Binding to cell lines was inhibited by EDTA and specific carbohydrate ligands, indicating involvement of the fibrinogen-like domain. Binding was enhanced under mildly acidic conditions and at physiological pH after pre-incubation of cells with mildly acidic buffer. ConclusionBasing on data concerning recombinant protein, it may be suggested that ficolin-3 is involved in immune response in ovarian cancer. However, unidentified serum factor(s) seem(s) to protect cancer cells from recognition by natural or rficolin-3.

Abstract PR04: Tumor-derived indoleamine 2,3-dioxygenase regulates density of tumor-infiltrating CD8+ T cells and myeloid-derived suppressor cells in a murine model of ovarian cancer

Abstract The catabolism of the essential amino-acid tryptophan by indoleamine 2,3-dioxygenase (IDO1) is a central pathway that contributes to an immunosuppressive microenvironment in many types of cancer. Our lab has previously shown that IDO1 expression in human ovarian tumor correlates with poor prognosis and poor tumor infiltration by CD8+ T cells, and that improved survival is associated with increased tumor-infiltrating lymphocytes. Thus, IDO1 inhibition represents an attractive target for cancer immunotherapy. To establish the mechanism by which IDO1 inhibition augments immune responses in a murine model of metastatic ovarian cancer, we generated a stable IDO1-overexpressing cell line (IE9mp1-mIDO1) and confirmed functional IDO1 enzyme activity. C57BL/6 mice were challenged intraperitoneally with IE9mp1-mIDO1 or IE9mp1-Empty Vector as a control. IE9mp1-mIDO1 tumor-bearing mice displayed earlier onset of tumor burden and decreased overall survival. To delineate the role of host- and tumor-derived IDO1 on immune cell infiltration in the tumor, IDO1 genetic knockout and C57BL/6 mice were challenged with IE9mp1-EV or -mIDO1 tumor cells. All mice challenged with IE9mp1-mIDO1 demonstrate decreased CD8+ T cells in the tumor compared to IDO1KO mice challenged with IE9mp1-EV tumor cells. Moreover, tumor-derived IDO1 mediates increased CD11b+Gr1+ myeloid derived suppressor cells (MDSC) in tumor ascites. From these data, we conclude that abrogation of IDO1 enzyme function will promote antitumor immune responses by permitting increased effector T cells decrease MDSCs in the tumor microenvironment. Ongoing experiments will characterize the mechanism by which IDO1 inhibition may augment vaccine-induced immune responses in ovarian cancer. This abstract is also being presented as Poster A19. Citation Format: Adaobi E. Amobi, Takemasa Tsuji, Robert McGray, Kunle Odunsi. Tumor-derived indoleamine 2,3-dioxygenase regulates density of tumor-infiltrating CD8+ T cells and myeloid-derived suppressor cells in a murine model of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR04.

Inhibiting the wnt/β-catenin pathway modulates immune response in ovarian cancer

Inhibiting the wnt/β-catenin pathway modulates immune response in ovarian cancer

Inhibiting the wnt/β-catenin pathway modulates immune response in ovarian cancer

Objective: The Wnt/β-catenin pathway mediates chemoresistance in ovarian cancer (OVCA) and is associated with immune exclusion via the non-T-cell-inflamed tumor phenotype across cancer types. Our objective was to investigate the inhibition of Wnt signaling in malignant human ascites cells and the immunomodulatory effect of Wnt inhibition using a syngeneic mouse model.

Abstract 1395: HDAC6 and DNMT inhibition affect immunogenicity of ovarian cancer cells: A rationale for combining epigenetic and immune therapy in ovarian cancer

Abstract Background: Therapies that activate the immune system to fight cancer have shown robust responses in solid tumors. However, most patients, including those with ovarian cancer, do not respond to these therapies alone. Drugs that inhibit epigenetic modifiers increase immune signaling from cancer cells. Epigenetic modifiers DNA methyltransferase inhibitors (DNMTi) and selective histone deacetylase inhibitors (HDACi),in particular selective HDAC6i, modulate immune-related pathways involved in anti-tumor immune responses. HDAC6i downregulate immunosuppressive ligands PD-L1 and PD-L2 via dephosphorylating pSTAT3 and upregulate tumor associated antigens (TAA) and antigen presentation machinery. Similarly, DNMTi activate anti-viral signaling via expression of Endogenous Retroviruses (ERVs) to trigger the type I interferon response, upregulate tumor antigen processing and presentation, and stimulate pro-inflammatory cytokines. The aim of our study is to test if the combination of epigenetic modulators Nexturastat A (Next A), a selective HDAC6i, and 5-azacytidine (AZA), a DNMTi, can be safely used to increase an immune response in ovarian cancer. We hypothesize that these drugs will enhance tumor immunity alone and when combined with immune checkpoint blockades targeting PD-1. Results: HDAC enzymes are differentially expressed in A2780, HEY, OVCAR3, SKOV3, and TYKNu human ovarian cancer cell lines. HDAC1 and HDAC2 proteins were similarly expressed in HEY and SKOV3 whereas HDAC6 was expressed at lower levels in HEY and TYKNu but at higher levels in SKOV3, OVCAR3, and A2780. As previously reported we believe this may be due to the presence of the chromatin modifier ARID1A mutation in the SKOV3 and A2780 cell lines. The upregulation of HDAC6 also correlated with a higher IC50 for NextA treatment in those particular cell lines. Further immunoblots showed that PD-L1, a marker of poor prognosis in ovarian cancer, decreased after treatment with NextA and even more in combination with AZA. Additionally, DNMT1, the known target of AZA, was decreased after treatment with AZA and NextA, both independently and in combination, a finding that has not been previously reported. Conclusions: As shown previously, HDAC6 enzyme levels are higher in cell lines with ARID1A mutations. DNMT1 was decreased after treatment with AZA, as expected, but surprisingly also after treatment with NextA. PD-L1 decreased after treatment with NextA and even more so when combined with AZA. We thus believe that combining these two epigenetic modifiers will lead to an additive effect on immune signaling through stimulation of antiviral signaling (DNMTi), which can upregulate the immunosuppressive ligand PD-L1, which is then reduced by HDAC6 inhibition. We are currently testing the combination of both epigenetic modifiers with anti-PD-1 in an immunocompetent mouse model of ovarian cancer. Citation Format: Aneil P. Srivastava, Sara M. Moufarrij, Melissa Hadley, Sarah Chisholm, Micael Lopez-Acevedo, Alejandro Villagra, Katherine B. Chiappinelli. HDAC6 and DNMT inhibition affect immunogenicity of ovarian cancer cells: A rationale for combining epigenetic and immune therapy in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1395.

Abstract LB-214: The immunosuppressive roles of ovarian stromal tumor microenvironment

Abstract Ovarian cancer is the most lethal gynecologic malignancy in the US. Our group and others has shown that CD8+ lymphocyte infiltration in the ovarian tumor epithelium is associated with prolonged survival in patients with high-grade serous ovarian cancer. Despite the increasing evidence on stromal involvement in tumor progression, the interactions between stromal fibroblasts and cancer cells, as well as the underlying genetic composition of the stromal cells that could regulate the infiltration and activation of CD8+ cytotoxic T lymphocytes (CTLs) and affect patient survival is not fully understood. The present study seeks to evaluate the roles and to delineate the underlying mechanisms by which stromal cancer associated fibroblasts (CAFs) modulates immune response in ovarian cancer, particularly immune suppression by CAF-derived protein factors. By laser microdissection and transcriptome profiling of tumor tissue samples from ovarian cancer patients, we identified CAF-specific gene signatures for ovarian cancer that are associated with the survival duration of patients and with the differential tumor immune response. Among the differentially expressed genes identified, validation study by qPCR and immunohistochemistry indicated that stromal MFAP5 expression is significantly higher in patients with short survival duration and in patients with lower intratumoral CD8+ T cell density. Survival analysis result suggested that high stromal MFAP5 expression indicates poor disease prognosis (Hazard ratio=2.722, P<0.001, N=102) and multiplex immunofluorescent staining result suggested that high stromal MFAP5 expression is associated with lower density of CD8+ / Granzyme B+ activated tumor-infiltrating CTLs (P=0.006). Our in vitro data suggested that stromal MFAP5 promotes ovarian cancer cell invasion, migration and chemoresistance. At the same, we showed that MFAP5 modulates the expression of immune-related genes and generate an immunosuppressive microenvironment through suppression of CD8+ T cell activation in the ovarian tumor tissue. Cell culture experiment results showed that MFAP5 protein treatment induced upregulation of CD47, an immune suppressive protein, in cancer cells and CD8+ T cells. Using an ovarian cancer-bearing immune competent animal model, we demonstrated that inhibition of stromal MFAP5-mediated signaling cascade suppressed tumor progression and promoted tumor immune response. Delineating the molecular mechanism by which MFAP5 modulates the progression and immune responses of ovarian cancer will shed light on the design of novel treatment modalities based on the blockade of tumor stroma-derived factors, which could promote activation and trafficking of cytotoxic CD8+ T cells and improve patient survival rates. Citation Format: Tsz-Lun Yeung, Cecilia S. Leung, Kwong-Kwok Wong, Michael J. Birrer, Stephen T. Wong, Karen H. Lu, Samuel C. Mok. The immunosuppressive roles of ovarian stromal tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-214. doi:10.1158/1538-7445.AM2017-LB-214

Tumor-derived indoleamine 2,3- dioxygenase regulates density of tumor infiltrating CD8+ T cells and myeloid derived suppressor cells in a murine model of ovarian cancer

Abstract The catabolism of the essential amino-acid tryptophan by indoleamine 2,3-dioxygenase (IDO1) is a central pathway that contributes to an immunosuppressive microenvironment in many types of cancer. Our lab has previously shown that IDO1 expression in human ovarian tumor correlates with poor prognosis and poor tumor infiltration by CD8+ T cells, and that improved survival is associated with increased tumor infiltrating lymphocytes. Thus, IDO1 inhibition represents an attractive target for cancer immunotherapy. To establish the mechanism by which IDO1 inhibition augments immune responses in a murine model of metastatic ovarian cancer, we generated a stable IDO1-overexpressing cell line (IE9mp1-mIDO1) and confirmed functional IDO1 enzyme activity. C57BL/6 mice were challenged intraperitoneally with IE9mp1-mIDO1 or IE9mp1-Empty Vector as a control. IE9mp1-mIDO1 tumor-bearing mice displayed earlier onset of tumor burden and decreased overall survival. To delineate the role of host- and tumor-derived IDO1 on immune cell infiltration in the tumor, IDO1 genetic knockout and C57BL/6 mice were challenged with IE9mp1-EV or -mIDO1 tumor cells. All mice challenged with IE9mp1-mIDO1 demonstrate decreased CD8+ T cells in the tumor compared to IDO1KO mice challenged with IE9mp1-EV tumor cells. Moreover, tumor-derived IDO1 mediates increased CD11b+Gr1+ myeloid derived suppressor cells (MDSC) in tumor ascites. From these data, we conclude that regulation of IDO1 will promote anti-tumor immune responses by permitting increased effector T cells in tumor tissues and decrease MDSCs in ascites. Ongoing experiments will characterize the mechanism by which IDO1 inhibition may augment vaccine-induced immune responses in ovarian cancer.

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

BackgroundOvarian cancer (OvCA) tissues show abundant expression of the ectonucleotidases CD39 and CD73 which generate immunomodulatory adenosine, thereby inhibiting cytotoxic lymphocytes. Little, however, is known about the effect of adenosine...

Abstract 4145: Stromal heterogeneity and immune response in ovarian cancer

Abstract Ovarian cancer is the most lethal gynecologic malignancy in the US. Our group and others has shown that CD8+ lymphocyte infiltration in the ovarian tumor epithelium is associated with prolonged survival in patients with high-grade serous ovarian cancer (HGSOC). Despite the increasing evidence on stromal involvement in tumor progression, the underlying genetic composition of the stromal cells that could regulate the infiltration and activation of CD8+ cytotoxic T lymphocytes (CTLs) in ovarian cancer is not fully understood. How tumor heterogeneity contributes to a different in immune response remains a challenge question that needs to be addressed. The present study seeks to evaluate the roles and to delineate the underlying mechanisms by which stromal cancer associated fibroblasts (CAFs) modulates immune response in ovarian cancer, particularly immune suppression by CAF-derived protein factors. By laser microdissection of tumor tissue samples from HGSOC patients, we generated cell type specific expression profiles and identified a CAF-specific gene signature for ovarian cancer. Genes expressed exclusively by CAFs that are associated with differential immune response were identified by comparing CAF expression profiles from HGSOC patients with high and low tumor-infiltrated CD8+ T cell densities. Among the differentially expressed genes identified, immunostaining results showed a significant inverse correlation between stromal MFAP5 expression and intratumoral CD8+ T cell density in HGSOC tissue samples (p = 0.006). The results were further confirmed by correlating stromal MFAP5 protein expression and intratumoral CD8+ T cell density. Our recent studies showed that increased stromal MFAP5 expression is associated with poorer survival in HGSOC patients and MFAP5 modulates ovarian caner invasion and motility potential. Together with our preliminary data showing that MFAP5 modulates the expression of immune-related genes, we hypothesize that stromal MFAP5 may generate an immunosuppressive microenvironment through suppressing CD8+ T cell activation and trafficking in the ovarian tumor tissue. Cell culture experiment showed that recombinant MFAP5 protein treatment induced expression of CD47, an immune checkpoint protein, in cancer cells and downregulated CXCL13, a chemokine essential for immune cell adhesion, in endothelial cells. Using animal models, these findings were further validated. Based on our data, animal studies will be performed to further evaluate the efficacy of immune activation by targeting stromal MFAP5 in ovarian cancer treatment. Delineating the molecular mechanism by which MFAP5 modulates the immune responses in ovarian cancer will help to design novel treatment modalities based on stromal MFAP5 blockade, which will promote activation and trafficking of cytotoxic CD8+ T cells and improve patient survival rates. Citation Format: Tsz-Lun Yeung, Cecilia S. Leung, Kwong-Kwok Wong, Samuel C. Mok. Stromal heterogeneity and immune response in ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4145.

Abstract A56: Inhibition of Snail-induced EMT promotes anti-tumor immune response in ovarian cancer.

Abstract Background: Peritoneal dissemination is a common mode of tumor progression in ovarian cancer, and one of the most important unfavorable prognostic factors. Epithelial-mesenchymal transition (EMT) has been indicated to be a key process in tumor invasion and metastasis. Recent studies demonstrate that EMT suppresses anti-tumor immunity in some types of cancer. The aim of the current study is to elucidate the relationship between EMT-related gene Snail and local immunity in ovarian cancer. Methods: The expression of Snail and patient survival was analyzed in two microarray datasets, TCGA, and KOV75 (75 ovarian cancer cases operated in our department). Using mouse ovarian cancer cell line HM-1, the influence of Snail expression on EMT, peritoneal dissemination, survival, and local immunity was analyzed using both in vitro and in vivo models. Snail-silenced cell line, HM1-sh-snail was established, and compared with the control HM-1. Results: Among 4 subtypes of high grade serous ovarian cancer, Mesenchymal subtype, which show marked stromal reaction in histopathology, shows the worst prognosis (TCGA, KOV75). Snail expression was significantly high in Mesenchymal subtype (TCGA, p<0.0001; KOV75, p<0.05). High Snail expression was significantly related to short overall survival in TCGA (p<0.05). In HM1-sh-snail, expression of vimentin and fibronectin was decreased in RT-PCR analysis. Cell migration was inhibited in wound-healing assay (p<0.001), but the cell proliferation was not altered in WST assay. In mouse peritoneal dissemination model, HM1-sh-snail group demonstrated longer survival than the control group (p<0.05). In mouse subcutaneous tumor model, HM-1-sh-snail group revealed smaller tumor than the control group (p<0.05), although there was no difference between two groups in nude mouse model. Flow cytometric analysis of mouse tumors revealed that infiltration of CD4+ T cells and CD8+ T cells were all increased and MDSCs were decreased in HM1-sh-snail group. Conclusion: Snail-induced EMT inhibits local immune reaction and promotes peritoneal dissemination in ovarian cancer. Snail may be a potential therapeutic target in ovarian cancer. Citation Format: Mana Taki, Kaoru Abiko, Noriomi Matsumura, Tsukasa Baba, Junzo Hamanishi, Naoki Horikawa, Ikuo Konishi. Inhibition of Snail-induced EMT promotes anti-tumor immune response in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A56.

A study of mature alpha-DC-1 vaccine to induce immune responses in ovarian cancer.

e14033 Background: Ovarian cancer (OvCa) is usually diagnosed at an advanced stage and relapse is common despite current treatments. The number of circulating CD4+ T regulatory cells (Tregs) correl...

Phase II trial of weekly nab-paclitaxel with GM-CSF as an immune modulator in recurrent platinum resistant ovarian, fallopian tube, and primary peritoneal cancer: Clinical and immune responses.

5580 Background: Antitumor immune responses in ovarian cancer have been associated with prolonged survival. In addition to direct cytotoxic activity, chemotherapies can also possess immunomodulator...

Autologous oxidized whole-tumor antigen vaccine in combination with angiogenesis blockade to elicit antitumor immune response in ovarian cancer.

5519 Background: Personalized tumor lysate vaccines can encompass all putative antigens in tumors. Methods: A pilot clinical trial was conducted using an autologous oxidized whole tumor cell lysate...

Plasma endothelial protein C receptor influences innate immune response in ovarian cancer by decreasing the population of natural killer and TH17 helper cells

In spite of the growing importance of endothelial protein C receptor/active protein C (EPCR/aPC) in tumor biology, their impact on immunological homeostasis remains largely unexplored. The objective of this study was to assess whether soluble plasma endothelial protein C receptor (sEPCR), which is a regulator of circulating aPC, is involved in innate immune response in cancer patients. In the Ovcar-3 ovarian cancer line, the role of aPC in secretion of cytokines was analyzed. In parallel, in 33 patients, with a diagnosis of ovarian epithelial cancer, sEPCR was quantified, blood immune cell phenotypes were determined by flow cytometry and plasma cytokines were evaluated using a protein array. Spearman's rank correlation coefficients (r) and coefficient significance was determined by a statistical hypothesis test (α=0.05). Our results show that i) aPC induced the secretion of several cytokines in Ovcar-3 cells; ii) 61% of patients exhibited a concentration of plasma sEPCR well above the baseline (normal plasma level, 100 ± 28 ng/ml); iii) comparing immune cell phenotypes in patients having a normal level of sEPCR with those having a high level of sEPCR, it was found that sEPCR levels were correlated with high intensity of cells expressing CD45ra, CD3, CD8, CD25 and low intensity of cells expressing CD56 (NK cells), CD294 (TH2 cells), IL-2, IL-10, IL-17a (TH17 cells), IL-21 (TH21 cells) and CD29 markers (r ≥ 0.60); and iv) high levels of sEPCR correlate with high levels of plasma bioactive proteins such as insulin-like growth factor-2 (IGFII), IL-13rα, macrophage inflammatory protein (MIP1α) and matrix metalloproteinase-7 (MMP-7) that have already been proposed as biomarkers for ovarian cancer and particularly those with poor prognosis. In conclusion, sEPCR produced by ovarian cancer cells, by modulating circulating aPC, influences the secretory behavior of tumor cells (cytokines and interleukins). Consequently, sEPCR in turn acts on the innate immune response by decreasing effector cells such as natural killer and T helper cells (TH2, TH17 and TH21).

Molecular Identification of GD3 as a Suppressor of the Innate Immune Response in Ovarian Cancer

Tumors often display mechanisms to avoid or suppress immune recognition. One such mechanism is the shedding of gangliosides into the local tumor microenvironment, and a high concentration of circulating gangliosides is associated with poor prognosis. In this study, we identify ganglioside GD3, which was isolated from the polar lipid fraction of ovarian cancer-associated ascites, as an inhibitory factor that prevents innate immune activation of natural killer T (NKT) cells. Purified GD3 displayed a high affinity for both human and mouse CD1d, a molecule involved in the presentation of lipid antigens to T cells. Purified GD3, as well as substances within the ascites, bound to the CD1d antigenic-binding site and did not require additional processing for its inhibitory effect on NKT cells. Importantly, in vivo administration of GD3 inhibited α-galactosylceramide (α-GalCer)-induced NKT cell activation in a dose-dependent manner. These data therefore indicate that ovarian cancer tumors may use GD3 to inhibit the antitumor NKT cell response as an early mechanism of tumor immune evasion.

Anti-tumor immune response in ovarian cancer: clinical implications, prognostic significance and potential for novel treatment strategies

Ovarian cancer is one of the leading causes of cancer-related death among women. Disease relapse occurs in a high number of cases and treatment currently involves the use of chemotherapy with the use of paclitaxel and platinum-based agents. Resistance to the disease occurs in more than 70% of the cases. The immune system is increasingly becoming a target for intense research in order to study the host’s immune response against ovarian cancer. T cell populations, including NK T cells and Tregs, have been associated with disease outcome indicating their increasing clinical significance, having been associated with positive prognosis and as markers of disease progress, respectively. Cytokines may also be associated with positive prognosis and they can have a direct or indirect effect in mobilizing relevant T cells, thus eliciting an immune response. Harnessing the immune system capacity in order to induce anti-tumor response is a major challenge. This is achieved via the use of antibodies that can elicit an immune response or via the use of direct administration of cytotoxic T cell populations (e.g., CD8?). This review examines the recent developments in our understanding of the mechanisms of development of the immune response in ovarian cancer as well as its prognostic significance and the existing experience in clinical studies using factors associated with immune response, such as monoclonal antibodies, cytokines, vaccines and activated or expanded relevant autologous populations from peripheral blood.

Anti-tumor immune response in ovarian cancer: clinical implications, prognostic significance and potential for novel treatment strategies

Anti-tumor immune response in ovarian cancer: clinical implications, prognostic significance and potential for novel treatment strategies

Analysis of the expression of human tumor antigens in ovarian cancer tissues

Biomarkers for early detection of cancer have great clinical diagnostic potential. Numerous reports have documented the generation of humoral immune responses that are triggered in response to changes in protein expression patterns in tumor tissues and these biomarkers are referred to as tumor associated antigens (TAAs). Using a high-throughput technology, we previously identified 65 proteins as diagnostically useful TAAs by profiling the humoral immune responses in ovarian cancer (OVCA) patients. Here we determined the expression status of some of those TAAs in tissues from OVCA patients. The protein expression patterns of 4 of those 65 antigens, namely NASP, RCAS1, Nijmegen breakage syndrome1 (NBS1) and eIF5A, along with p53 and Her2 (known molecular prognosticators) and two proteins that interact with NBS1, MRE11 and RAD50, were assessed by immunohistochemistry (IHC). NASP and RCAS1 proteins were more frequently expressed in ovarian cancer tissues than with normal ovarian tissue and serous cystadenomas and MRE11 was less frequently expressed. When evaluated simultaneously, only NASP and MRE11 remained statistically significant with sensitivity of 66% and specificity of 89%. None of these proteins' expression levels were prognostic for survival. Together, our results indicate that occurrence of humoral immune responses against some of these TAAs in OVCA patients is triggered by antigen protein overexpression.

Immune response in ovarian cancer: how is the immune system involved in prognosis and therapy: potential for treatment utilization.

Ovarian cancer is one of the leading causes of cancer-related death among women. Resistance to the disease occurs in more than 70% of the cases even after treated with chemotherapy agents such as paclitaxel- and platinum-based agents. The immune system is increasingly becoming a target for intense research in order to study the host's immune response against ovarian cancer. T cell populations, including NK T cells and Tregs, and cytokines have been associated with disease outcome, indicating their increasing clinical significance, having been associated with prognosis and as markers of disease progress, respectively. Harnessing the immune system capacity in order to induce antitumor response remains a major challenge. This paper examines the recent developments in our understanding of the mechanisms of development of the immune response in ovarian cancer as well as its prognostic significance and the existing experience in clinical studies.