Methionine consumption by cancer cells drives a progressive upregulation of PD-1 expression in CD4 T cells

Author:

Pandit Mahesh,Kil Yun-Seo,Ahn Jae-Hee,Pokhrel Ram Hari,Gu Ye,Mishra Sunil,Han Youngjoo,Ouh Yung-TaekORCID,Kang Ben,Jeong Myeong Seon,Kim Jong-OhORCID,Nam Joo-WonORCID,Ko Hyun-JeongORCID,Chang Jae-HoonORCID

Abstract

AbstractProgrammed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker. The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. Reduced methionine increases PD-1 expression on CD4 T cells. The genetic ablation of SLC43A2 in cancer cells restores methionine metabolism in CD4 T cells, increasing the intracellular levels of S-adenosylmethionine and yielding H3K79me2. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in CD4 T cells. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Our results demonstrate that AMPK is a methionine-dependent regulator of the epigenetic control of PD-1 expression in CD4 T cells, a metabolic checkpoint for CD4 T cell exhaustion.

Funder

National Research Foundation of Korea

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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