PRMT1 mediated methylation of cGAS suppresses anti-tumor immunity

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.


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Life sciences study design
All studies must disclose on these points even when the disclosure is negative. The customized genomic analysis was based on The Cancer Genome Atlas (TCGA) data (https://cancergenome.nih.gov/). The data for PRMT1 expression and survival of patients with bladder cancer after PD-L1 antibody treatment were generated using the TIDE tool (http://tide.dfci.harvard.edu) and the source data are based on the Mariathasan2018_PDL1cohort. The association between PRMT1 expression level and T cell dysfunction in multiple cancer types were generated using the TIDE tool and the source data are derived from data in TCGA and PRECOG. The expression data of cGAS and PD-L1 in a panel of BRCA cell lines were obtained from GEO dataset GSE73526. RNA-seq data used to support the present study have been deposited in the Gene Expression Omnibus (GSE203466). The expression data of cGAS and PD-L1 were obtained from GEO dataset GSE73526.
For animal experiments, 15 mice have been used in each group according to previous study in the lab (PMID: 31270456, PMID: 32839551, PMID: 33909988).
For the syngeneic mouse model experiments, those mice without tumor at day 7 after implantation were excluded, and then all mice were randomly assigned into different treatment groups. For figure 7a, a total of 8 mice were excluded due to failure in tumor implantation. For Figure 7c, atotal of 9 mice were excluded.
All biochemical experiments were repeated at least 3 times and all animal works in Figure 5 and 7 were repeated twice unless otherwise indicated, and all attempts at replication were successful.
Animal were randomly grouped before treatment. Randomization is not relevant to other experiments.
No blinding is applicable to the study, as all cell and animal treatment conditions and groups are clear to the researchers. All antibodies used in this study were obtained from reputable commercial vendors.
Biolegend: "Antibody clones are then tested in a variety of assays to see which applications they are suited for....Thus, the clone cross-validates itself by demonstrating functionality across orthogonal testing methods." Cell Signaling Technology: "This product has met all of the quality control standards defined by Cell Signaling Technology, Inc." Abcam: "Our Abpromise guarantee covers the use of it in the following tested applications." Sigma :"SSigma-Aldrich warrants, that at the time of the quality release or subsequent retest date this product conformed to the information contained in this publication. " All cell lines were authenticated.

MDA
All cells were tested and validated for mycoplasma-free.
No commonly misidentified cell lines were used in the study.

Female
This study did not involved samples collected from the field.