Age-induced succinate dysmetabolism promotes Tregulatory cells in Ovarian Cancer 3543

Abstract Description Ovarian cancer (OvCa), the deadliest gynecologic cancer, primarily affects women over 60, with a median diagnosis age of 63 years. Aging reduces naïve T cell production and increases immunosuppressive regulatory T (Treg) cells, linked to advanced stage and poor prognosis in multiple cancer types. Aging also alters metabolism, affecting Treg function, but the association to immune activity remains unclear. In our study, young (2 months) and old (18 months) female C57/B6 mice were injected with OvCa cells. Older OvCa mice had reduced survival compared to younger mice, with a significant increase in Treg abundance, enhanced IL-10 and TGF-β expression, and greater suppression of CD4+ T cells. Treg depletion improved survival, with a more pronounced effect in older mice. Tregs from older OvCa mice exhibited increased oxidative phosphorylation (OXPHOS) and glycolysis. Targeted metabolomics revealed a significant increase in succinate levels in Tregs, tumors, and ascitic fluid. Succinate treatment enhanced Treg immunosuppressive function, increasing IL-10 and TGF-β while reducing CD4+ T cell proliferation. Inhibition of succinate synthesis in tumor cells from aged OvCa mice using CPI-613, an alphaketoglutarate dehydrogenase complex inhibitor reversed IL-10 and TGF-β upregulation, restoring CD4+ T cell proliferation. These studies show that an aged microenvironment dysregulates succinate levels, boosting Treg immunosuppressive function and promoting tumor growth in older OvCa mice. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)