Abstract 3642: SPHK1 mediated regulation of antitumor immunity in ovarian cancer

Abstract Introduction: Sphingosine kinase 1 (SPHK1) is an enzyme that helps to synthesize biolipid sphingosine-1-phosphate (S1P). We showed extracellular vesicles facilitate an increased accumulation of S1P in the ovarian tumor microenvironment (TME). S1P enhances the exhaustion of CD8 T cells, thus downregulating anti-tumor immunity. Furthermore, we also found less ovarian tumor burden in SPHK1−/− mice compared to WT mice. Based on our preliminary data, we hypothesized that the SPHK1 depleted tumor microenvironment increases the infiltration of the immune cells and its activity downregulates the tumor progression. Methods: SPHK1 global knockout mice and WT C57BL/6 mice were used in the study. Tumor cells (ID8 P53−/− BRCA−/−) were injected, and tumor progression was studied. Immunophenotyping was performed by flow cytometry on ascites and tumor samples. Activation of CD8 T cells, B cells, and dentritic cells were studied by flow cytometry. Bulk RNA sequencing was performed on SPHK1−/− and WT tumors. Results: SPHK1−/− mice showed regression in tumor growth in multiple tumor models. Tumor tissues from SPHK1−/− mice enhanced infiltration of CD4 and CD8 T cells, B cells, and dentritic cells compared to WT mice. Furthermore, infiltrated immune cells were active in SPHK1−/− mice. Bulk RNA sequencing also showed enhanced immune response in SPHK1−/− tumors compared to WT tumors. Conclusion: SPHK1−/- environment decreased the tumor growth by enhancing the infiltration and activation of immune cells. We are currently focusing on identifying the immune cells which are critical players in this process. We will further implement these findings in human immune cells for clinical benefits for ovarian cancer patients. Citation Format: Prachi Gupta, Sudhir Kumar, Ishaque Pulikkal Kadamberi, Sonam Mittal, Jasmine George, Anjali Geethadevi, Pradeep Chaluvally-Raghavan, Sunila Pradeep. SPHK1 mediated regulation of antitumor immunity in ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3642.