PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity

Jing Liu, Xia Bu, Chen Chu, Xiaoming Dai, John M. Asara, Piotr Sicinski, Gordon J. Freeman () and Wenyi Wei ()
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Jing Liu: Beth Israel Deaconess Medical Center, Harvard Medical School
Xia Bu: Dana-Farber Cancer Institute, Harvard Medical School
Chen Chu: Dana-Farber Cancer Institute
Xiaoming Dai: Beth Israel Deaconess Medical Center, Harvard Medical School
John M. Asara: Harvard Medical School
Piotr Sicinski: Dana-Farber Cancer Institute
Gordon J. Freeman: Dana-Farber Cancer Institute, Harvard Medical School
Wenyi Wei: Beth Israel Deaconess Medical Center, Harvard Medical School

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Activation of the cGAS/STING innate immunity pathway is essential and effective for anti-tumor immunotherapy. However, it remains largely elusive how tumor-intrinsic cGAS signaling is suppressed to facilitate tumorigenesis by escaping immune surveillance. Here, we report that the protein arginine methyltransferase, PRMT1, methylates cGAS at the conserved Arg133 residue, which prevents cGAS dimerization and suppresses the cGAS/STING signaling in cancer cells. Notably, genetic or pharmaceutical ablation of PRMT1 leads to activation of cGAS/STING-dependent DNA sensing signaling, and robustly elevates the transcription of type I and II interferon response genes. As such, PRMT1 inhibition elevates tumor-infiltrating lymphocytes in a cGAS-dependent manner, and promotes tumoral PD-L1 expression. Thus, combination therapy of PRMT1 inhibitor with anti-PD-1 antibody augments the anti-tumor therapeutic efficacy in vivo. Our study therefore defines the PRMT1/cGAS/PD-L1 regulatory axis as a critical factor in determining immune surveillance efficacy, which serves as a promising therapeutic target for boosting tumor immunity.

Date: 2023
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DOI: 10.1038/s41467-023-38443-3

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