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bioRxiv · 10.1101/2025.08.07.668717

Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment

Rattan, R.·Udumula, M. P.·KM, A.·Rashid, F.·Nematullah, M.·Singh, H.·Bhardwaj, T.·Hijaz, M.·Giri, S.·Chini, E. N.·Gibson, H. M.
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Abstract

Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg)-mediated immunosuppression. In aged EOC-bearing mice, we observed reduced survival, accompanied by impaired CD4 and CD8T cell responses and a marked expansion of FOXP3 Tregs exhibiting elevated IL-10 and TGF{beta} expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of -ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate driven metabolic reprogramming as a central mechanism of age related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.

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Rattan, R., Udumula, M. P., KM, A., Rashid, F., Nematullah, M., Singh, H., Bhardwaj, T., Hijaz, M., Giri, S., Chini, E. N., Gibson, H. M.. 2025-08-11. Aging-Driven Immunosuppression: The Role of Tregs in the Ovarian Tumor Microenvironment. https://doi.org/10.1101/2025.08.07.668717

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