METTL3-mediated m6A RNA methylation promotes the anti-tumour immunity of natural killer cells

Hao Song; Jiaxi Song; Ming Cheng; Meijuan Zheng; Tian Wang; Sha Tian; Richard A Flavell; Shu Zhu; Hua-Bing Li; Chen Ding; Haiming Wei; Rui Sun; Hui Peng; Zhigang Tian

doi:10.1038/s41467-021-25803-0

METTL3-mediated m⁶A RNA methylation promotes the anti-tumour immunity of natural killer cells

Nat Commun. 2021 Sep 17;12(1):5522. doi: 10.1038/s41467-021-25803-0.

Authors

Hao Song^{1

2}, Jiaxi Song^{1

2}, Ming Cheng^{1

2}, Meijuan Zheng³, Tian Wang^{1

2}, Sha Tian⁴, Richard A Flavell^{5

6}, Shu Zhu^{1

2}, Hua-Bing Li⁷, Chen Ding⁴, Haiming Wei^{1

2}, Rui Sun^{1

2}, Hui Peng^{8

9}, Zhigang Tian^{10

11

12}

Affiliations

¹ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China.
² Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230027, China.
³ Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, 230022, China.
⁴ State Key Laboratory of Genetic Engineering, Human Phenome Institute, Institutes of Biomedical Sciences, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.
⁵ Department of Immunobiology, Yale University School of Medicine, New Haven, CT, 06520, USA.
⁶ Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
⁷ Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
⁸ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. huipeng@ustc.edu.cn.
⁹ Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230027, China. huipeng@ustc.edu.cn.
¹⁰ Hefei National Laboratory for Physical Sciences at Microscale, the CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China. tzg@ustc.edu.cn.
¹¹ Institute of Immunology, University of Science and Technology of China, Hefei, Anhui, 230027, China. tzg@ustc.edu.cn.
¹² Research Unit of NK Cell Study, Chinese Academy of Medical Sciences, Hefei, Anhui, 230027, China. tzg@ustc.edu.cn.

Abstract

Natural killer (NK) cells exert critical roles in anti-tumor immunity but how their functions are regulated by epitranscriptional modification (e.g., N⁶-methyladenosine (m⁶A) methylation) is unclear. Here we report decreased expression of the m⁶A "writer" METTL3 in tumor-infiltrating NK cells, and a positive correlation between protein expression levels of METTL3 and effector molecules in NK cells. Deletion of Mettl3 in NK cells alters the homeostasis of NK cells and inhibits NK cell infiltration and function in the tumor microenvironment, leading to accelerated tumor development and shortened survival in mice. The gene encoding SHP-2 is m⁶A modified, and its protein expression is decreased in METTL3-deficient NK cells. Reduced SHP-2 activity renders NK cells hyporesponsive to IL-15, which is associated with suppressed activation of the AKT and MAPK signaling pathway in METTL3-deficient NK cells. These findings show that m⁶A methylation safeguards the homeostasis and tumor immunosurveillance function of NK cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine / analogs & derivatives*
Adenosine / metabolism
Animals
Carcinogenesis / pathology
Cell Line, Tumor
Gene Deletion
Homeostasis
Interleukin-15 / metabolism
Killer Cells, Natural / immunology*
Lymphocytes, Tumor-Infiltrating / immunology
Methylation
Methyltransferases / deficiency
Methyltransferases / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Neoplasms / immunology*
Neoplasms / metabolism*
Protein Tyrosine Phosphatase, Non-Receptor Type 11 / metabolism
Proto-Oncogene Proteins c-akt / metabolism
RNA / metabolism*
Signal Transduction
Tumor Microenvironment

Substances

Interleukin-15
RNA
N-methyladenosine
Methyltransferases
Mettl3 protein, mouse
Proto-Oncogene Proteins c-akt
Protein Tyrosine Phosphatase, Non-Receptor Type 11
Ptpn11 protein, mouse
Adenosine