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VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells Irina V

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VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells Irina V Published OnlineFirst April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2518 Biology of Human Tumors Clinical Cancer Research VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells Irina V. Tiper1, Sarah M. Temkin2,3, Sarah Spiegel1, Simeon E. Goldblum2, Robert L. Giuntoli II3, Mathias Oelke4, Jonathan P. Schneck4, and Tonya J. Webb1 Abstract Purpose: Natural killer T (NKT) cells are important mediators Results: Ovarian cancer tissue and ascites contain lym- of antitumor immune responses. We have previously shown that phocytic infiltrates, suggesting that immune cells trafficto ovarian cancers shed the ganglioside GD3, which inhibits NKT- tumors, but are then inhibited by immunosuppressive mole- cell activation. Ovarian cancers also secrete high levels of VEGF. In cules within the tumor microenvironment. OV-CAR-3 this study, we sought to test the hypothesis that VEGF production and SK-OV-3 cell lines produce high levels of VEGF and by ovarian cancers suppresses NKT-cell–mediated antitumor GD3. Pretreatment of APCs with ascites or conditioned responses. medium from OV-CAR-3 and SK-OV-3 blocked CD1d-medi- Experimental Design: To investigate the effects of VEGF on ated NKT-cell activation. Inhibition of VEGF resulted in a CD1d-mediated NKT-cell activation, a conditioned media model concomitant reduction in GD3 levels and restoration of was established, wherein the supernatants from ovarian cancer NKT-cell responses. cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d- Conclusions: We found that VEGF inhibition restores NKT-cell expressing antigen-presenting cells (APC) and cocultured with function in an in vitro ovarian cancer model. These studies suggest NKT hybridomas. Ovarian cancer–associated VEGF was inhibited that the combination of immune modulation with antiangio- by treatment with bevacizumab and genistein; conditioned medi- genic treatment has therapeutic potential in ovarian cancer. um was collected, and CD1d-mediated NKT-cell responses were Clin Cancer Res; 22(16); 4249–58. Ó2016 AACR. assayed by ELISA. Introduction of patients with advanced ovarian cancer remain less than 50% (3, 4). The lack of effective treatment options for relapse requires In the United States, ovarian cancer is the fifth most common the development of alternative interventions against this recalci- cause of cancer-related death among women (1). In fact, trant disease. >120,000 women worldwide die each year from this disease that In ovarian cancer, immune function is central to response to has the highest fatality-to-incidence of all gynecologic malignan- treatment and prognosis (5–11). Several groups have reported cies (2). The major clinical challenge for this disease is that a that long-term survivors (>10 years) have higher levels of T-cell majority of patients present with late-stage disease, and 70% of infiltrates in their tumors. However, the immune response is more patients have stage III or IV disease at the time of diagnosis. nuanced. The presence or absence of specific T-cell subsets has Despite improvements in treatment, even with aggressive cytor- been correlated to survival (7). Tumor infiltration by regulatory T eduction combined with chemotherapy, 5-year survival rates þ þ cells (Treg; CD4 CD25 T cells) is indicative of reduced survival, þ whereas the presence of intraepithelial CD8 T cells is associated with favorable prognosis in ovarian cancer (8). 1Department of Microbiology and Immunology, University of Maryland Escape from the host's immune system is crucial for cancer School of Medicine, Baltimore, Maryland. 2Department of Medicine, growth and development of metastasis. Identification of immu- University of Maryland School of Medicine, Baltimore, Maryland. nosuppressive factors produced within the tumor microenviron- 3Department of Gynecology and Obstetrics, The Kelly Gynecologic Oncology Service,The Sidney Kimmel Comprehensive Cancer Center, ment and the ability to target these factors could enhance anti- The Johns Hopkins School of Medicine, Baltimore, Maryland. 4Depart- tumor immune responses. Several studies have focused on tumor- ment of Pathology,The Johns Hopkins School of Medicine, Baltimore, associated immune suppression mediated by Tregs, myeloid- Maryland. derived suppressor cells, immunosuppressive dendritic cells, Note: Supplementary data for this article are available at Clinical Cancer immune-inhibitory receptors, and inhibitory factors, including Research Online (http://clincancerres.aacrjournals.org/). TGFb, prostaglandins, and adenosine (12–17). In addition, com- Corresponding Author: Tonya J. Webb, University of Maryland School of ponents of ovarian ascites fluid have also been shown to inhibit Medicine, 685 W. Baltimore St, HSF-I, Room 380, Baltimore, MD 21201. Phone: immune function (18). Recently, it was reported that phospha- 410-706-4109; Fax: 410-706-6970; E-mail: [email protected] tidylserine present in extracellular vesicles harvested from ovarian doi: 10.1158/1078-0432.CCR-15-2518 tumor ascites fluids and from solid ovarian tumors induces TCR Ó2016 American Association for Cancer Research. signaling arrest (19). In addition, we have shown that ganglioside www.aacrjournals.org 4249 Downloaded from clincancerres.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst April 13, 2016; DOI: 10.1158/1078-0432.CCR-15-2518 Tiper et al. land Medical Center approved this investigation. Ovarian cancer Translational Relevance samples were obtained from the tissue bank, and 4-mm sections of VEGF inhibition has become important in the treatment of paraffin-embedded tissues were deparaffinized and rehydrated ovarian cancer. VEGF expression is inversely correlated with and an antigen-retrieval procedure performed according to the survival in patients with ovarian cancer. Ovarian cancer–asso- manufacturer's instructions using Target-Retrieval Solution ciated ascites contain much higher levels of VEGF compared (DAKO). with ascites found in patients with other solid tumors. Bev- acizumab, an mAb that binds to VEGF and prevents the Cell lines interaction of VEGF with its receptors, has demonstrated Human ovarian cancer cells, SK-OV-3, and endometrial cancer activity in the treatment of recurrent and metastatic ovarian cell line, HEC-1A, were cultured in McCoy's 5a Modified Medium cancer. Bevacizumab is also useful in palliation of ascites in supplemented with 10% FBS and penicillin/streptomycin. OV- patients with advanced and recurrent ovarian cancer where CAR-3, purchased from the ATCC, was grown in in RPMI1640 ascites is a hallmark of disease. As avoiding detection by the medium supplemented with 20% FBS, 0.01 mg/mL bovine insu- host's immune system is crucial for the growth and metastasis lin, and penicillin/streptomycin. The cell lines were used within 6 – of cancer, we sought to examine the effects of ovarian cancer months of purchase. associated VEGF on CD1d-mediated antigen presentation to Murine L cells transfected with vector alone (Lvector) or the WT natural killer T (NKT) cells. We found that inhibiting VEGF cd1d1 cDNA in pcDNA3.1-neo (Invitrogen; LCD1dwt) were kind- secretion by ovarian cancer cell lines restored NKT-cell activa- ly provided by R.R. Brutkiewicz (Indiana University School of tion. Herein, we demonstrate a novel link between immuno- Medicine, Indianapolis, IN; ref. 31) and were cultured in DMEM suppressive ganglioside shedding and VEGF production by media, supplemented with 2 mmol/L L-glutamine, 10% FBS, ovarian cancers. By establishing a mechanism through which 500 mg/mL G418, and penicillin/streptomycin. The cell lines used VEGF impairs antitumor immune responses, our studies have have been tested and authenticated routinely by staining for stable the potential to enhance the clinical therapeutic possibilities cell surface expression of CD1d, compared with isotype control for women with this disease. staining, and also compared with cells stably transfected with the empty control vector. þ The Va14 NKT-cell hybridoma cell lines DN32.D3, (32, 33), N38-2C12, N38-2H4, N38-3C3, and the CD1d-specific NKT-cell þ (GD3) produced by ovarian cancer cells is present in ascites fluid hybridoma N37-1A12 (Va5 ), have all been described previously and can inhibit antitumor natural killer T (NKT)-cell responses (34) and were cultured in IMDM medium supplemented with 5% (20). Similarly, it has been reported that higher levels of gang- FBS and 2 mmol/L L-glutamine. The NKT cells are tested for liosides, specifically GD3, are present in sera of ovarian cancer specificity to CD1d in each experiment via functional T-cell assay. patients compared with healthy donors due to ganglioside shed- ding from the surface of tumor cells (21). VEGF inhibition VEGF levels in the ascites of patients with ovarian cancer are VEGF was purchased from Sigma (#V7259) and reconstituted much higher (up to 10-fold higher) than levels in ascites as per manufacturer's instructions. Genistein was purchased from associated with other solid tumors (22). These high ascites Sigma (#G6649) and reconstituted in DMSO. Bevacizumab/ VEGF levels in patients with ovarian cancer have also been Avastin (Genentech) was supplied reconstituted by the manufac- shown to be inversely correlated with survival (23, 24), corre- turer in water supplemented with salts. OV-CAR-3 cells were late directly with invasion and metastasis of ovarian cancer seeded in a flask, allowed to grow to 70% confluence, and cells, and further play a role in the formation of ovarian cancer– subsequently
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