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

Mahesh Pandit, Yun-Seo Kil, Jae-Hee Ahn, Ram Hari Pokhrel, Ye Gu, Sunil Mishra, Youngjoo Han, Yung-Taek Ouh, Ben Kang, Myeong Seon Jeong, Jong-Oh Kim, Joo-Won Nam, Hyun-Jeong Ko () and Jae-Hoon Chang ()
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Mahesh Pandit: Yeungnam University
Yun-Seo Kil: Yeungnam University
Jae-Hee Ahn: Kangwon National University
Ram Hari Pokhrel: Yeungnam University
Ye Gu: Yeungnam University
Sunil Mishra: Yeungnam University
Youngjoo Han: Kangwon National University
Yung-Taek Ouh: Kangwon National University
Ben Kang: Kyungpook National University
Myeong Seon Jeong: Korea Basic Science Institute (KBSI)
Jong-Oh Kim: Yeungnam University
Joo-Won Nam: Yeungnam University
Hyun-Jeong Ko: Kangwon National University
Jae-Hoon Chang: Yeungnam University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Programmed 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.

Date: 2023
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DOI: 10.1038/s41467-023-38316-9

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