FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma

Abstract

Regulatory Tcells overwhelm conventional Tcells in the tumor microenvironment (TME) thanks to a FOXP3-driven metabolic program that allows them to engage different metabolic pathways. Using a melanoma model of adoptive Tcell therapy (ACT), we show that FOXP3 overexpression in mature CD8 Tcells improved their antitumor efficacy, favoring their tumorrecruitment, proliferation, and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 Tcells exhibited features of tissue-resident memory-like and effector Tcells, but not suppressor activity. Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 Tcells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism, and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 Tcells exhibited an enhanced capacity for glucose and FA uptake as well as accumulation of intracellular lipids. Interestingly, Foxp3UP CD8 Tcells compensated for the loss of mitochondrial respiration-driven ATP production by activating aerobic glycolysis. Moreover, in limiting nutrient conditions these cells engaged FA oxidation to drive OXPHOS for their energy demands. Importantly, their ability to couple glycolysis and OXPHOS allowed them to sustain proliferation under glucose restriction. Our findings demonstrate a hitherto unknown role for FOXP3 in the adaptation of CD8 Tcells to TME that may enhance their efficacy in ACT.