Abstract 851: Uncovering a novel role of succinate metabolism in tregulatory cells of aged epithelial ovarian cancer mice
Authors: Udumula Mary Priyanka , Singh Harshit , Rashid Faraz , Hijaz Miriana , Giri Shailendra , Rattan Ramandeep 
Published: March 2024

Epithelial Ovarian Cancer (EOC), the most fatal gynecologic cancer is a disease of older women, with median age of 63 years at diagnosis. Reduced naive T cell generation and a rise in immunosuppressive regulatory T (Treg) cells are hallmarks of aging, which are strongly correlated with advanced cancer stage. Aging also alters host and cellular metabolism, which can influence Treg number and function. Although metabolic alterations are known to impact ant-tumor immune response, the relationship between age-related metabolic dysfunction and immune cells is not fully understood. We utilized young (2 months) and old (18 months) female C57/B6 mice, and were injected intraperitoneally with 5 × 106 mouse epithelial ovarian cancer ID8p53-/− cells. Old mice with EOC showed decreased survival compared to young mice (median survival 49 vs 65 days). Old mice with EOC presented with decreased CD4+ and CD8+ T cells, but a significant increase in CD4+CD25+FoxP3+ Treg cells in tumor micro environment (TME) and in blood. The Tregs from old mice displayed enhanced expression of IL10 and TGFβ, which corelated with their increased suppression of CD4 and CD8 T cells compared to Tregs isolated from young EOC mice. The CD4+ and CD8+ T cells also displayed decreased effector makers including CD4+IFNγ, CD8+IFNγ and CD8+ Granzyme B, compared to young EOC mice in TME and in blood. The tumor promoting role of Treg was validated by depleting Tregs using anti-CD25 antibody which resulted in decreased tumor burden and improved overall survival, of both young and old mice, more significantly in old EOC mice. Tregs from old mice with EOC displayed enhanced metabolic activity, reflected in increased oxidative phosphorylation (OXPHOS) compared to young EOC mice. Further, on inhibition of OXPHOS, the Tregs from old mice showed decreased expression of immunosuppressive markers Foxp3 and IL10. Targeted metabolomics of TCA cycle in the Tregs, revealed a 5-fold increase in succinate levels in old EOC Tregs compared to young. Succinate treatment enhanced the immunosuppressive Treg function along with an increase in levels of IL10 and TGFβ, while inhibition of succinate synthesis reversed the increase in FOXP3, IL10 and TGFβ. We identified fibroblast growth factor 21 (FGF-21), a hormone essential for T cell development, to be significantly decreased in ascites and plasma, of old mice. Supplementing FGF21 decreased Treg survival, number, and suppressive ability, resulting in increased CD4+ and CD8+ cells in aged EOC mice. FGF21 treatment decreased OXPHOS and succinate levels in aged Tregs. Overall, our observations indicate Tregs to be vital in driving aggressive EOC in old mice. The hyper-suppressive Tregs in old mice reprogram succinate metabolism to drive their suppressive ability which may be negatively regulated by FGF21. Thus, Treg-succinate-FGF21 may be a potential actionable pathway in precision targeting of EOC in the older population.

Citation Format: Mary Priyanka Udumula, Harshit Singh, Faraz Rashid, Miriana Hijaz, Shailendra Giri, Ramandeep Rattan. Uncovering a novel role of succinate metabolism in tregulatory cells of aged epithelial ovarian cancer mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 851.