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Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells
Irina V Tiper1, Sarah M Temkin2, Sarah Spiegel1
1Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, Maryland.
Purpose:
Natural killer T (NKT) cells are important mediators of antitumor immune responses. We have previously shown that ovarian cancers shed the ganglioside GD3, which inhibits NKT-cell activation. Ovarian cancers also secrete high levels of VEGF. In this study, we sought to test the hypothesis that VEGF production by ovarian cancers suppresses NKT-cell-mediated antitumor responses.
Experimental Design:
To investigate the effects of VEGF on CD1d-mediated NKT-cell activation, a conditioned media model was established, wherein the supernatants from ovarian cancer cell lines (OV-CAR-3 and SK-OV-3) were used to treat CD1d-expressing antigen-presenting cells (APC) and cocultured with NKT hybridomas. Ovarian cancer-associated VEGF was inhibited by treatment with bevacizumab and genistein; conditioned medium was collected, and CD1d-mediated NKT-cell responses were assayed by ELISA.
Results:
Ovarian cancer tissue and ascites contain lymphocytic infiltrates, suggesting that immune cells traffic to tumors, but are then inhibited by immunosuppressive molecules within the tumor microenvironment. OV-CAR-3 and SK-OV-3 cell lines produce high levels of VEGF and GD3. Pretreatment of APCs with ascites or conditioned medium from OV-CAR-3 and SK-OV-3 blocked CD1d-mediated NKT-cell activation. Inhibition of VEGF resulted in a concomitant reduction in GD3 levels and restoration of NKT-cell responses.
Conclusions:
We found that VEGF inhibition restores NKT-cell function in an in vitro ovarian cancer model. These studies suggest that the combination of immune modulation with antiangiogenic treatment has therapeutic potential in ovarian cancer. Clin Cancer Res; 22(16); 4249-58. ©2016 AACR.
Insights
Vascular Endothelial Growth Factor (VEGF) suppresses Natural Killer T (NKT) cell antitumor responses in ovarian cancer. Inhibiting VEGF restores NKT cell function, suggesting combined immunotherapy and antiangiogenic treatment potential.
Area of Science:
- Immunology
- Oncology
Background:
- Natural Killer T (NKT) cells are crucial for antitumor immunity.
- Ovarian cancers produce ganglioside GD3, inhibiting NKT cell activation.
- Ovarian cancers also secrete high levels of Vascular Endothelial Growth Factor (VEGF).
Purpose of the Study:
- To investigate the hypothesis that VEGF suppresses NKT cell-mediated antitumor responses in ovarian cancer.
- To determine if VEGF inhibition can restore NKT cell function.
Main Methods:
- Utilized a conditioned media model with ovarian cancer cell lines (OV-CAR-3, SK-OV-3).
- Treated antigen-presenting cells (APCs) with cancer cell supernatants and cocultured with NKT hybridomas.
- Inhibited VEGF using bevacizumab and genistein, then assayed NKT cell responses via ELISA.
Main Results:
- Ovarian cancer ascites and conditioned media blocked CD1d-mediated NKT cell activation.
- VEGF and GD3 were highly produced by ovarian cancer cell lines.
- Inhibiting VEGF reduced GD3 levels and restored NKT cell responses.
Conclusions:
- VEGF inhibition restores NKT cell function in an in vitro ovarian cancer model.
- Combination of immune modulation and antiangiogenic therapy shows therapeutic potential for ovarian cancer.
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