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

Pandit, Mahesh; Kil, Yun-Seo; Ahn, Jae-Hee; Pokhrel, Ram Hari; Gu, Ye; Mishra, Sunil; Han, Youngjoo; Ouh, Yung-Taek; Kang, Ben; Jeong, Myeong Seon; Kim, Jong-Oh; Nam, Joo-Won; Ko, Hyun-Jeong; Chang, Jae-Hoon

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. The deprivation of amino acids in the tumor microenvironment affects T cell survival and activation. Here the authors show that reduced levels of methionine are associated with PD1 upregulation in CD4 T cells and that methionine supplementation promotes CD4 T cell dependent anti-tumor immune responses.

CANCER cells; T-cell exhaustion; CD4 antigen; SLEEP deprivation; PROGRAMMED cell death 1 receptors; METHIONINE; METHIONINE metabolism; ENDOPLASMIC reticulum; T cells

Nature Communications, 2023, Vol 14, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-023-38316-9