journal contribution
posted on 2024-02-01, 08:22 authored by Hongru Tao, Chen Jin, Liyuan Zhou, Zhenzhong Deng, Xiao Li, Wenzhen Dang, Shijie Fan, Bing Li, Fei Ye, Junyan Lu, Xiangqian Kong, Chuanpeng Liu, Cheng Luo, Yuanyuan Zhang This file includes all supplemental data with figure legends.
Funding
National Natural Science Foundation of China (NSFC)
Science and Technology Commission of Shanghai Municipality (STCSM)
National Key Research and Development Program of China (NKPs)
State Key Laboratory of Respiratory Disease (SKLRD)
Lingang Laboratory
National Administration of Traditional Chinese Medicine
High-level new R&D institute
High-level Innovative Research Institute
History
ARTICLE 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 methyltransferase 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 derived from endogenous retroviral elements (ERV) 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.
Targeting PRMT1 stimulates interferon signaling by increasing expression of endogenous retroviral elements and double-stranded RNA through repression of DNMT1, which induces antitumor immunity and synergizes with immunotherapy to suppress tumor progression.
