Abstract 2161: Fasting fueled ketogenesis inhibits ovarian cancer and promotes anti-tumor T cell response

Abstract

Abstract Epithelial Ovarian Cancer (EOC) is the most lethal gynecologic cancer with no predominant genetic alteration identified that can be therapeutically targeted. Low-cost non-toxic approaches such as dietary modulations alter the responses of host and the cancer cells. Limited scientific investigations have examined the link between nutrition and EOC. Here, we tested the outcome of intermittent fasting (IF) on EOC progression with focus on fasting driven anti-tumor immune responses. Female C57/B6 mice were injected intraperitoneally with 5x106 mouse epithelial ovarian cancer ID8 (p53-/-, ID8 p53-/-, PTEN-/- and ID8 p53-/-, BRCA-/-) cells and fed either ad libitum (RD) or subjected to IF, where they underwent 16 hour fasting and 8 hour feeding window for 5 days/week. Tumor progression was monitored by ascites formation and abdominal circumference. Immune profiling was performed by flow cytometry using BD FACS Calibur. Untargeted metabolomics was performed in plasma from RD and IF mice using LC-MS/MS. Enhancement of immunotherapy was tested by combining IF with anti-PD 1 (100 µg/mice, every 5th day, 3 times) in ID8 p53-/- tumor bearing mice and similar parameters were examined. IF reduced the growth of ID8 (p53-/-, ID8 p53-/-, PTEN-/- and ID8 p53-/-, BRCA-/-) tumors, increased overall survival when compared to RD mice. IF promoted anti-tumor T cell response as seen by increase in CD4+ and CD8+ cells with enhanced expression of IFNγ, granzyme B and perforin compared to RD mice bearing ID8 cells in the ascites and blood. A striking observation was that the CD4+ T cells from IF mice exhibited a strong Th1 phenotype (CD4+IFNγ+), while Th2 phenotype (CD4+IL4+) was significantly decreased. IF when combined with anti-PD-1 treatment significantly improved survival and potentiated the T cell mediated anti-tumor response. Metabolic analysis revealed an enrichment in ketone body biosynthetic pathway as reflected by 5fold increase in serum ketone bodies such as beta hydroxy butyrate (BHB) and acetoacetate, when compared to RD. Receptors that have been reported to response to BHB as a ligand, specifically GPR109A and GPR41, were highly expressed on T cells derived from IF mice. BHB treatment enhanced the CD8+ T cell effector function as reflected by increased levels of IFNγ, granzyme B and perforin compared to untreated CD8+ T cells. Our study shows that IF significantly restricts EOC growth, improve survival, potentiate chemotherapy and immunotherapy anti-tumor response by augmenting T cell mediated anti-tumor immune responses. We also provide evidence that IF generated bioactive metabolite BHB which can be a potential substitute for availing the ant-tumor benefits of IF. Thus, our data provides strong evidence for IF and its metabolic mediator BHB for ameliorating EOC progression and as a viable approach in maintaining and sustaining an effective anti-tumor T cell response alone and in combination with immunotherapy. Citation Format: Mary Priyanka Udumula, Laila Poisson, Lin Chun-Hui, Nivedita Tiwari, Harshit Singh, Giri Shailendra, Ramandeep Rattan. Fasting fueled ketogenesis inhibits ovarian cancer and promotes anti-tumor T cell response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2161.