Journal
CANCER IMMUNOLOGY RESEARCH
Volume 10, Issue 4, Pages 420-436Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-21-0614
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Funding
- NCI [R01CA187076, P50CA221703, P30CA016672]
- Melanoma Research Alliance Young Investigator Award [558998]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- Aim at Melanoma Foundation
- Aim at Melanoma Foundation, Miriam and Jim Mulva research funds
- Cancer Prevention and Research Institute of Texas [CPRIT RP170401, RP200520]
- NIH [R01GM126421]
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Protein arginine methyltransferases play crucial roles in cancer progression, with inhibition of type I PRMTs increasing T-cell infiltration and inducing durable anti-tumor responses in immunotherapy.
Protein arginine methyltransferases (PRMT) are a widely expressed class of enzymes responsible for catalyzing arginine methylation on numerous protein substrates. Among them, type I PRMTs are responsible for generating asymmetric dimethylarginine. By controlling multiple basic cellular processes, such as DNA damage responses, transcriptional regulation, and mRNA splicing, type I PRMTs contribute to cancer initiation and progression. A type I PRMT inhibitor, GSK3368715, has been developed and has entered clinical trials for solid and hematologic malignancies. Although type I PRMTs have been reported to play roles in modulating immune cell function, the immunologic role of tumor-intrinsic pathways controlled by type I PRMTs remains uncharacterized. Here, our The Cancer Genome Atlas dataset analysis revealed that expression of type I PRMTs associated with poor clinical response and decreased immune infiltration in patients with melanoma. In cancer cell lines, inhibition of type I PRMTs induced an IFN gene signature, amplified responses to IFN and innate immune signaling, and decreased expression of the immunosuppressive cytokine VEGF. In immunocompetent mouse tumor models, including a model of T-cell exclusion that represents a common mechanism of anti- programmed cell death protein 1 (PD-1) resistance in humans, type I PRMT inhibition increased T-cell infiltration, produced durable responses dependent on CD8 thorn T cells, and enhanced efficacy of anti-PD-1 therapy. These data indicate that type I PRMT inhibition exhibits immunomodulatory properties and synergizes with immune checkpoint blockade (ICB) to induce durable antitumor responses in a T cell-dependent manner, suggesting that type I PRMT inhibition can potentiate an antitumor immunity in refractory settings.
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