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

doi:10.1158/2159-8290.CD-22-1301

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 journal › Article › peer-review

14 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 language	English (US)
Pages (from-to)	2566-2583
Number of pages	18
Journal	Cancer Discovery
Volume	13
Issue number	12
DOIs	https://doi.org/10.1158/2159-8290.CD-22-1301
State	Published - Dec 1 2023

All Science Journal Classification (ASJC) codes

Oncology

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10.1158/2159-8290.CD-22-1301

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Rowe, J. H., Elia, I., Shahid, O., Gaudiano, E. F., Sifnugel, N. E., Johnson, S., Reynolds, A. G., Fung, M. E., Joshi, S., Lafleur, M. W., Park, J. S., Pauken, K. E., Rabinowitz, J. D., Freeman, G. J., Haigis, M. C., & Sharpe, A. H. (2023). Formate Supplementation Enhances Antitumor CD8⁺ T-cell Fitness and Efficacy of PD-1 Blockade. Cancer Discovery, 13(12), 2566-2583. https://doi.org/10.1158/2159-8290.CD-22-1301

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

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.",

author = "Rowe, {Jared H.} and Ilaria Elia and Osmaan Shahid and Gaudiano, {Emily F.} and Sifnugel, {Natalia E.} and Sheila Johnson and Reynolds, {Amy G.} and Fung, {Megan E.} and Shakchhi Joshi and Lafleur, {Martin W.} and Park, {Joon Seok} and Pauken, {Kristen E.} and Rabinowitz, {Joshua D.} and Freeman, {Gordon J.} and Haigis, {Marcia C.} and Sharpe, {Arlene H.}",

note = "Publisher Copyright: {\textcopyright} 2023 American Association for Cancer Research.",

year = "2023",

month = dec,

day = "1",

doi = "10.1158/2159-8290.CD-22-1301",

language = "English (US)",

volume = "13",

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Rowe, JH, Elia, I, Shahid, O, Gaudiano, EF, Sifnugel, NE, Johnson, S, Reynolds, AG, Fung, ME, Joshi, S, Lafleur, MW, Park, JS, Pauken, KE, Rabinowitz, JD, Freeman, GJ, Haigis, MC & Sharpe, AH 2023, 'Formate Supplementation Enhances Antitumor CD8⁺ T-cell Fitness and Efficacy of PD-1 Blockade', Cancer Discovery, vol. 13, no. 12, pp. 2566-2583. https://doi.org/10.1158/2159-8290.CD-22-1301

TY - JOUR

T1 - Formate Supplementation Enhances Antitumor CD8+ T-cell Fitness and Efficacy of PD-1 Blockade

AU - Rowe, Jared H.

AU - Elia, Ilaria

AU - Shahid, Osmaan

AU - Gaudiano, Emily F.

AU - Sifnugel, Natalia E.

AU - Johnson, Sheila

AU - Reynolds, Amy G.

AU - Fung, Megan E.

AU - Joshi, Shakchhi

AU - Lafleur, Martin W.

AU - Park, Joon Seok

AU - Pauken, Kristen E.

AU - Rabinowitz, Joshua D.

AU - Freeman, Gordon J.

AU - Haigis, Marcia C.

AU - Sharpe, Arlene H.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - 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.

AB - 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.

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ER -

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

Abstract

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