封锁
癌症研究
医学
干扰素
黑色素瘤
免疫检查点
免疫
免疫学
免疫系统
药理学
内科学
受体
作者
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
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2023-11-22
卷期号:84 (3): 419-433
被引量:3
标识
DOI:10.1158/0008-5472.can-23-1082
摘要
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. Significance: 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.
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