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

• Published in: Molecular therapy 2023-01, Vol.31 (1), p.48-65
• Main Authors: Conde, Enrique, Casares, Noelia, Mancheño, Uxua, Elizalde, Edurne, Vercher, Enric, Capozzi, Roberto, Santamaria, Eva, Rodriguez-Madoz, Juan R., Prosper, Felipe, Lasarte, Juan J., Lozano, Teresa, Hervas-Stubbs, Sandra
• Format: Article
• Language: English
• Subjects: CD8 T cell response; CD8-Positive T-Lymphocytes - immunology; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; FOXP3; Glucose - metabolism; Humans; Immunotherapy, Adoptive; Melanoma - therapy; Original; T cell metabolism; T cell-based cancer immunotherapy; Tumor Microenvironment
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2022.08.017

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. [Display omitted] FOXP3 overexpression in mature CD8 T cells improves their antitumor efficacy in adoptive T cell therapy, favoring their metabolic adaptation to the tumor microenvironment as well as their recruitment, proliferation, and cytotoxicity within tumors. FOXP3-overexpressing CD8 T cells exhibit features of tissue-resident memory-like and effector T cells, but not suppressor activity.