Faculty, Staff and Student Publications
Publication Date
12-12-2023
Journal
Cancer Discovery
Abstract
UNLABELLED: 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.
SIGNIFICANCE: 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.
Keywords
Humans, Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, Neoplasms, Formates, Dietary Supplements, Tumor Microenvironment, One carbon metabolism, formate, PHGDH, immune metabolism, anti-PD-1, anti-tumor immunity, immune checkpoint blockade, tumor microenvironment
DOI
10.1158/2159-8290.CD-22-1301
PMID
37728660
PMCID
PMC10843486
PubMedCentral® Posted Date
June 2024
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Included in
Biochemical Phenomena, Metabolism, and Nutrition Commons, Bioinformatics Commons, Biomedical Informatics Commons, Medical Cell Biology Commons, Medical Immunology Commons, Oncology Commons