Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade

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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2566-2583
Number of pages18
JournalCancer Discovery
Volume13
Issue number12
DOIs
StatePublished - Dec 1 2023

All Science Journal Classification (ASJC) codes

  • Oncology

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