FOXP3 expression diversifies the metabolic capacity and enhances the efficacy of CD8 T cells in adoptive immunotherapy of melanoma
Enrique Conde 1 , Noelia Casares 1 , Uxua Mancheño 1 , Edurne Elizalde 1 , Enric Vercher 1 , Roberto Capozzi 1 , Eva Santamaria 2 , Juan R Rodriguez-Madoz 3 , Felipe Prosper 4 , Juan J Lasarte 1 , Teresa Lozano 5 , Sandra Hervas-Stubbs 6
Regulatory T cells overwhelm conventional T cells 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 T-cell therapy (ACT), we show that FOXP3 overexpression in mature CD8 T cells improved their antitumor efficacy, favoring their tumor recruitment, proliferation and cytotoxicity. FOXP3-overexpressing (Foxp3UP) CD8 T cells exhibited features of tissue-resident memory-like and effector T cells, but not suppressor activity.
Transcriptomic analysis of tumor-infiltrating Foxp3UP CD8 T cells showed positive enrichment in a wide variety of metabolic pathways, such as glycolysis, fatty acid (FA) metabolism and oxidative phosphorylation (OXPHOS). Intratumoral Foxp3UP CD8 T cells exhibited an enhanced capacity for glucose and FA uptake, as well as accumulation of intracellular lipids.
Interestingly, Foxp3UP CD8 T cells 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 T cells to TME that may enhance their efficacy in ACT.
CITATION Mol Ther. 2023 Jan 4;31(1):48-65. doi: 10.1016/j.ymthe.2022.08.017. Epub 2022 Aug 31