journal contribution
posted on 2023-12-12, 08:20 authored by Jared H. Rowe, Ilaria Elia, Osmaan Shahid, Emily F. Gaudiano, Natalia E. Sifnugel, Sheila Johnson, Amy G. Reynolds, Megan E. Fung, Shakchhi Joshi, Martin W. LaFleur, Joon Seok Park, Kristen E. Pauken, Joshua D. Rabinowitz, Gordon J. Freeman, Marcia C. Haigis, Arlene H. Sharpe Supplementary Figure 8 shows a diagram of the CD8 depletion strategy and individual growth curves from CD8 depleted mice in main Figure 4.
Funding
Roche (Roche Holding)
Ludwig Center (HMS)
Office of Extramural Research, National Institutes of Health (OER)
Glenn Foundation for Medical Research (GFMR)
Cancer Research Institute (CRI)
European Molecular Biology Organization (EMBO)
History
ARTICLE ABSTRACT
The tumor microenvironment (TME) restricts antitumor CD8+ T-cell function and immunotherapy responses. Cancer cells compromise the metabolic fitness of CD8+ T cells within the TME, but the mechanisms are largely unknown. Here we demonstrate that one-carbon (1C) metabolism is enhanced in T cells in an antigen-specific manner. Therapeutic supplementation of 1C metabolism using formate enhances CD8+ T-cell fitness and antitumor efficacy of PD-1 blockade in B16-OVA tumors. Formate supplementation drives transcriptional alterations in CD8+ T-cell metabolism and increases gene signatures for cellular proliferation and activation. Combined formate and anti–PD-1 therapy increases tumor-infiltrating CD8+ T cells, which are essential for enhanced tumor control. Our data demonstrate that formate provides metabolic support to CD8+ T cells reinvigorated by anti–PD-1 to overcome a metabolic vulnerability in 1C metabolism in the TME to further improve T-cell function.
This study identifies that deficiencies in 1C metabolism limit the efficacy of PD-1 blockade in B16-OVA tumors. Supplementing 1C metabolism with formate during anti–PD-1 therapy enhances CD8+ T-cell fitness in the TME and CD8+ T-cell–mediated tumor clearance. These findings demonstrate that formate supplementation can enhance exhausted CD8+ T-cell function.See related commentary by Lin et al., p. 2507.This article is featured in Selected Articles from This Issue, p. 2489
