Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy

Kaixin Wu; Sa Li; Guangliang Hong; Hongzhi Dong; Tongke Tang; He Liu; Lingmei Jin; Siyuan Lin; Jingyun Ji; Mingli Hu; Shuntian Chen; Haoyuan Wu; Guanzheng Luo; Haoyuan Wu; Xiangqian Kong; Jiekai Chen; Jiangping He; Hongling Wu

doi:10.1002/ctm2.70089

Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (11) : e70089 DOI: 10.1002/ctm2.70089

RESEARCH ARTICLE

Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy

Kaixin Wu ¹^,²^,³^,^†
, Sa Li ⁴^,⁵
, Guangliang Hong ⁶
, Hongzhi Dong ⁴
, Tongke Tang ⁴
, He Liu ¹^,²
, Lingmei Jin ⁴^,⁵
, Siyuan Lin ⁶
, Jingyun Ji ⁷
, Mingli Hu ⁴^,⁸
, Shuntian Chen ³
, Haoyuan Wu ³
, Guanzheng Luo ⁷
, Haoyuan Wu ⁴
, Xiangqian Kong ⁴
, Jiekai Chen ¹^,³^,⁴^,⁹
, Jiangping He ²^,⁶^,^†
, Hongling Wu ⁴^,¹⁰

Author information +

¹. Center for Cell Lineage and Atlas, Bioland Laboratory, Guangzhou Regenerative Medicine and Health GuangDong Laboratory, Guangzhou, China

². The Fifth Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

³. Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou Medical University, Guangzhou, China

⁴. Center for Cell Lineage and Development, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China

⁵. University of Chinese Academy of Sciences, Beijing, China

⁶. Guangzhou National Laboratory, Guangzhou, China

⁷. MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-Sen University, Guangzhou, China

⁸. Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China

⁹. Centre for Regenerative Medicine and Health, Hong Kong Institute of Science & Innovation, Chinese Academy of Sciences, Hong Kong SAR, China

¹⁰. State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China

wu_kaixin123@163.com

he_jiangping@gzlab.ac.cn

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Abstract

	•Targeting METTL3 augments tumour cell immunogenicity and sustains T-cell function.
	•T cell with METTL3 inhibition can reverse T-cell exhaustion, and promote expression of IFNγ and GzmB, thereby enhancing cytotoxicity in anti-PD-1 therapy.
	•YTHDF2 deletion in tumours prolong the lifespan of MHC-I mRNAs.

Keywords

B16 melanoma / immunotherapy / METTL3 / N6-methyladenosine (m6A) / T-cell function / YTHDF2

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Kaixin Wu, Sa Li, Guangliang Hong, Hongzhi Dong, Tongke Tang, He Liu, Lingmei Jin, Siyuan Lin, Jingyun Ji, Mingli Hu, Shuntian Chen, Haoyuan Wu, Guanzheng Luo, Haoyuan Wu, Xiangqian Kong, Jiekai Chen, Jiangping He, Hongling Wu. Targeting METTL3 as a checkpoint to enhance T cells for tumour immunotherapy. Clinical and Translational Medicine, 2024, 14(11): e70089 DOI:10.1002/ctm2.70089

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.