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 () and Zhigang Tian ()
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Hao Song: University of Science and Technology of China
Jiaxi Song: University of Science and Technology of China
Ming Cheng: University of Science and Technology of China
Meijuan Zheng: The First Affiliated Hospital of Anhui Medical University
Tian Wang: University of Science and Technology of China
Sha Tian: Fudan University
Richard A. Flavell: Yale University School of Medicine
Shu Zhu: University of Science and Technology of China
Hua-Bing Li: Shanghai Jiao Tong University School of Medicine
Chen Ding: Fudan University
Haiming Wei: University of Science and Technology of China
Rui Sun: University of Science and Technology of China
Hui Peng: University of Science and Technology of China
Zhigang Tian: University of Science and Technology of China

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-25803-0

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