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Fedoriw, Andrew; Shi, Leilei; O'Brien, Shane; Smitheman, Kimberly N.; Wang, Yunfei; Hou, Jiakai; Sherk, Christian; Rajapurkar, Satyajit; Laraio, Jenny; Williams, Leila J.; Xu, Chunyu; Han, Guangchun; Feng, Qin; Bedford, Mark T.; Wang, Linghua; Barbash, Olena; Kruger, Ryan G.; Hwu, Patrick; Mohammad, Helai P.; Peng, Weiyi

Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell–Mediated Antitumor Immune Responses

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  • Media type: E-Article
  • Title: Inhibiting Type I Arginine Methyltransferase Activity Promotes T Cell–Mediated Antitumor Immune Responses
  • Contributor: Fedoriw, Andrew; Shi, Leilei; O'Brien, Shane; Smitheman, Kimberly N.; Wang, Yunfei; Hou, Jiakai; Sherk, Christian; Rajapurkar, Satyajit; Laraio, Jenny; Williams, Leila J.; Xu, Chunyu; Han, Guangchun; Feng, Qin; Bedford, Mark T.; Wang, Linghua; Barbash, Olena; Kruger, Ryan G.; Hwu, Patrick; Mohammad, Helai P.; Peng, Weiyi
  • Published: American Association for Cancer Research (AACR), 2022
  • Published in: Cancer Immunology Research, 10 (2022) 4, Seite 420-436
  • Language: English
  • DOI: 10.1158/2326-6066.cir-21-0614
  • ISSN: 2326-6066; 2326-6074
  • Origination:
  • Footnote:
  • Description: Abstract 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+ 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.
  • Access State: Open Access