Journal Article

Cancer SLC43A2 alters T cell methionine metabolism and histone methylation

Kryczek, Ilona, Li, Wei, Pawłowska, Anna, Yu, Jiali, Bian, Yingjie, Wertel, Iwona, Liao, Peng, McLean, Karen, Lyssiotis, Costas A., Li, Shasha, Zou, Weiping, Sajjakulnukit, Peter, Nwosu, Zeribe C., Crespo, Joel, Vatan, Linda, Cieslik, Marcin, Szeliga, Wojciech, Zhang, Li, Grove, Sara, Li, Jing, Xia, Houjun, Liu, J. Rebecca, Kremer, Daniel M., Chinnaiyan, Arul M., Okła, Karolina, Wei, Shuang, Wallner, Grzegorz, Czerwonka, Arkadiusz, Zgodziński, Witold

2020

Overview

Abnormal epigenetic patterns correlate with effector T cell malfunction in tumours 1 – 4 , but the cause of this link is unknown. Here we show that tumour cells disrupt methionine metabolism in CD8 + T cells, thereby lowering intracellular levels of methionine and the methyl donor S -adenosylmethionine (SAM) and resulting in loss of dimethylation at lysine 79 of histone H3 (H3K79me2). Loss of H3K79me2 led to low expression of STAT5 and impaired T cell immunity. Mechanistically, tumour cells avidly consumed methionine and outcompeted T cells for methionine by expressing high levels of the methionine transporter SLC43A2. Genetic and biochemical inhibition of tumour SLC43A2 restored H3K79me2 in T cells, thereby boosting spontaneous and checkpoint-induced tumour immunity. Moreover, methionine supplementation improved the expression of H3K79me2 and STAT5 in T cells, and this was accompanied by increased T cell immunity in tumour-bearing mice and patients with colon cancer. Clinically, tumour SLC43A2 correlated negatively with T cell histone methylation and functional gene signatures. Our results identify a mechanistic connection between methionine metabolism, histone patterns, and T cell immunity in the tumour microenvironment. Thus, cancer methionine consumption is an immune evasion mechanism, and targeting cancer methionine signalling may provide an immunotherapeutic approach. Expression of the transporter SLC43A2 by tumour cells allows them to outcompete T cells for methionine and thereby disrupt the survival and function of tumour-infiltrating T cells.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/2 / 13/21 / 13/31 / 38/23 / 38/90 / 631/250/580 / 631/67/2327 / 82/29 / Adenosylmethionine / Amino Acid Transport System L - deficiency / Amino Acid Transport System L - metabolism / Amino acids / Analysis / Animals / Apoptosis / Cancer / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / Cell Line, Tumor / Colon / Colon cancer / Colorectal cancer / Cytokines / DNA methylation / Epigenesis, Genetic / Epigenetics / Female / Gene expression / Genetic aspects / Glucose / Histone H3 / Histones / Histones - chemistry / Histones - metabolism / Humanities and Social Sciences / Humans / Immunity / Influence / Intracellular levels / Lymphocytes / Lymphocytes T / Lysine / Metabolism / Metabolites / Methionine / Methionine - metabolism / Methods / Methylation / Mice / multidisciplinary / Neoplasms - genetics / Neoplasms - immunology / Neoplasms - metabolism / Neoplasms - pathology / Physiology / Receptors, Antigen, T-Cell - metabolism / Science / Science (multidisciplinary) / Stat5 protein / STAT5 Transcription Factor - metabolism / Supplements / T cell receptors / T cells / Tumor microenvironment / Tumors