Background Although immunotherapy produced dramatic clinical responses in a certain population of cancer patients, tumor cells can employ a variety of immunosuppressive measures to limit the immunotherapeutic efficacy. This highlights a great need to develop novel strategies to expand the clinical benefits of immunotherapy to a broader population of cancer patients. PRMTs have been described as vital regulators of immune responsive pathways in several cell types, but the immunoregulatory role of Type I PRMTs in the tumor microenvironment remains poorly understood.

Methods In this study, we analyzed the correlation between Type I PRMT expression levels with the clinical outcome or immune signature. Gene expression changes were evaluated in a panel of immunogenic and non-immunogenic cancer cell lines with Type I PRMT inhibitor treatment. The antitumor and immunological effects of Type I PRMT inhibitor were evaluated in combination with checkpoint blockade in a panel of syngeneic tumor models.

Results Using TCGA dataset analysis, increased mRNA expression levels of several Type I PRMTs were associated with poor clinical response and decreased immune infiltration in melanoma patients. Particularly, tumors with high expression of PRMT1, the major Type I PRMTs, displayed significantly reduced relapse-free survival (HR=1.891, p=0.038), and were associated with lower cytolytic score (logFC=-0.875, p=1.49e-08) and lower lymphocyte infiltration score (logFC=-0.783, p=0.00077). RNA-seq results showed that interferon signaling was significantly altered after Type I PRMT inhibitor treatment in 10 of 15 cell lines analyzed, with most related genes showing increased expression. In addition, VEGFA was downregulated by 25% or more in 7/8 human and 3/5 mouse cancer cell lines, and a moderate decrease in chromatin accessibility at the Vegfa promoter was observed in ATAC-seq data. Furthermore, Type I PRMT inhibitor combined with anti-PD1 treatment significantly extended the survival of tumor-bearing mice and delayed tumor growth in a panel of immunocompetent mouse models. Mechanistically, Type I PRMT inhibitor significantly increased the apoptotic sensitivity of tumor cells to autologous tumor-reactive T cells in vitro and the infiltration of total T cells (CD3+) in 3 of 4 tested tumor models and cytotoxic T cells (CD8+) in two tested tumor models in vivo.

Conclusions Taken together, these data indicated that Type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade to induce durable antitumor responses in a T cell dependent manner. This study provides a rationale to combine Type I PRMT inhibitor with immune checkpoint blockade to maximize clinical benefits in cancer patients.

Acknowledgements The authors would like to thank past and present members of the MDACC TIL lab for tumor/TIL processing and banking.