Methionine Deficiency Facilitates Antitumour Immunity by Altering MA Methylation of Immune Checkpoint Transcripts

Overview

Journal Gut

Specialty Gastroenterology

Date 2022 Jul 8

PMID 35803704

Authors

Ting Li

Yue-Tao Tan

Yan-Xing Chen

Xiao-Jun Zheng

Wen Wang

Kun Liao

Hai-Yu Mo

Junzhong Lin

Wei Yang

Hai-Long Piao

Rui-Hua Xu

Huai-Qiang Ju

Affiliations

Soon will be listed here.

Abstract

Objective: Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined.

Design: The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated.

Results: We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8 T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N-methyladenosine (mA) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or mA-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8 T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients.

Conclusions: Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.

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