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, Jae‐Hoon Chang
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.