![]() T cells are a focal point for activating the immune system against cancer, particularly owing to their capacity for antigen-directed cytotoxicity 4.ĬD4 T cells show efficacious antitumor immunity by helping CD8 cytotoxic T lymphocytes (CTLs) or by direct antitumor activity 5, 6. Metabolic changes and a nutrient-deficient environment in the TME promote tumor growth and impair antitumor immunity, exhausting T cells 2, 3. Therefore, the TME has always been a nutrition-competitive environment for cancer cells and immune cells. 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.Ĭancer cells import large amounts of nutrients from the tumor microenvironment (TME) to support biosynthetic demands associated with their survival and proliferation 1. AMPK-deficient CD4 T cells exhibit increased endoplasmic reticulum stress and Xbp1s transcript levels. Methionine supplementation restores H3K79 methylation and AMPK expression, lowering PD-1 levels. Reduced H3K79me2 due to methionine deprivation downregulates AMPK, upregulates PD-1 expression and impairs antitumor immunity in 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 methionine increases PD-1 expression on CD4 T cells. Here we develop nutrient-deprived media and a conditional knockout female mouse model to study the mechanism underlying PD-1 upregulation. ![]() The mechanisms underlying PD-1 upregulation in CD4 T cells remain unknown. Programmed cell death protein 1 (PD-1), expressed on tumor-infiltrating T cells, is a T cell exhaustion marker.
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