2. Academic Validation
  3. PRMT1 inhibition activates the interferon pathway to potentiate antitumor immunity and enhance checkpoint blockade efficacy in melanoma

PRMT1 inhibition activates the interferon pathway to potentiate antitumor immunity and enhance checkpoint blockade efficacy in melanoma

  • Cancer Res. 2023 Nov 22. doi: 10.1158/0008-5472.CAN-23-1082.
Hongru Tao 1,  Chen Jin 2,  Liyuan Zhou 3,  Zhenzhong Deng 4,  Xiao Li 5,  Wenzhen Dang 5,  Shijie Fan 6,  Bing Li 7,  Fei Ye 8,  JunYan Lu 9,  Xiangqian Kong 10,  Chuanpeng Liu 11,  Cheng Luo 7,  Yuanyuan Zhang 12
Affiliations

Affiliations

  • 1 Harbin Institute of Technology, Harbin, China.
  • 2 Nanjing University of Chinese Medicine, nanjing, China.
  • 3 Hangzhou Institute for Advanced Study, Hangzhou, China.
  • 4 Shanghai Jiao Tong University, China.
  • 5 Hangzhou Institute for Advanced Study, China.
  • 6 Zhongshan Institute for Drug Discovery, China.
  • 7 Shanghai Institute of Materia Medica, China.
  • 8 Zhejiang Sci-Tech University, China.
  • 9 Heidelberg University, Heidelberg, Baden-Württemberg, Germany.
  • 10 Guangzhou Institutes of Biomedicine and Health, China.
  • 11 Harbin Institute of Technology, China.
  • 12 Shanghai Institute of Materia Medica, Shanghai, China.
PMID: 37991725 DOI: 10.1158/0008-5472.CAN-23-1082
Abstract

Despite the immense success of immune checkpoint blockade (ICB) in Cancer treatment, many tumors, including melanoma, exhibit innate or adaptive resistance. Tumor-intrinsic T-cell deficiency and T-cell dysfunction have been identified as essential factors in the emergence of ICB resistance. Here, we found that protein arginine methyl transferase 1 (PRMT1) expression was inversely correlated with the number and activity of CD8+ T cells within melanoma specimen. PRMT1 deficiency or inhibition with DCPT1061 significantly restrained refractory melanoma growth and increased intratumoral CD8+T cells in vivo. Moreover, PRMT1 deletion in melanoma cells facilitated formation of double-stranded RNA (dsRNA) derived from endogenous retroviral elements (ERVs) and stimulated an intracellular interferon response. Mechanistically, PRMT1 deficiency repressed the expression of DNA Methyltransferase 1 (DNMT1) by attenuating modification of H4R3me2a and H3K27ac at enhancer regions of DNMT1, and DNMT1 downregulation consequently activated ERV transcription and the interferon signaling. Importantly, PRMT1 inhibition with DCPT1061 synergized with PD-1 blockade to suppress tumor progression and increase the proportion of CD8+T cells as well as IFNγ+CD8+T cells in vivo. Together, these results reveal an unrecognized role and mechanism of PRMT1 in regulating antitumor T-cell immunity, suggesting PRMT1 inhibition as a potent strategy to increase the efficacy of ICB.

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