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

被引:16
作者
Rowe, Jared H. [1 ,2 ,3 ]
Elia, Ilaria [4 ,5 ]
Shahid, Osmaan [2 ,3 ]
Gaudiano, Emily F. [2 ,3 ]
Sifnugel, Natalia E. [2 ,3 ]
Johnson, Sheila [4 ]
Reynolds, Amy G. [1 ]
Fung, Megan E. [2 ,3 ]
Joshi, Shakchhi [4 ]
LaFleur, Martin W. [2 ,3 ]
Park, Joon Seok [2 ,3 ]
Pauken, Kristen E. [2 ,3 ]
Rabinowitz, Joshua D. [6 ]
Freeman, Gordon J. [7 ]
Haigis, Marcia C. [4 ]
Sharpe, Arlene H. [2 ,3 ]
机构
[1] Dana Farber Canc Inst, Dept Pediat Oncol, Boston, MA USA
[2] Blavatnik Inst, Harvard Med Sch, Dept Immunol, Boston, MA USA
[3] Lay Inst Immunol & Inflammat, Harvard Med Sch & Brigham & Womens Hosp, Boston, MA USA
[4] Blavatnik Inst, Harvard Med Sch, Dept Cell Biol, Boston, MA USA
[5] Dept Cellular & Mol Med, Leuven, Belgium
[6] Princeton Univ, Lewis Sigler Inst Integrat Genom, Princeton, NJ USA
[7] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA USA
基金
美国国家卫生研究院;
关键词
ONE-CARBON METABOLISM; TUMOR MICROENVIRONMENT; SACCHAROMYCES-CEREVISIAE; NIVOLUMAB; SERINE; ACTIVATION; IPILIMUMAB;
D O I
10.1158/2159-8290.CD-22-1301
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Metabolic support, in the form of formate supplementation, combined with anti-PD-1 improves antitumor CD8+ T-cell fitness and tumor control, revealing a strategy that can be used to extend the benefits of anti-PD-1 therapy. 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. 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
引用
收藏
页码:2566 / 2583
页数:18
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