Protein arginine methyltransferase 5 (PRMT5) controls diverse cellular processes and is implicated in cancer development and progression. Here, we report an inverse correlation between PRMT5 function and antitumor immunity. PRMT5 expression was associated with an antitumor immune gene signature in human melanoma tissue. Reducing PRMT5 activity antagonized melanoma growth in immunocompetent but not immunocompromised mice. PRMT5 methylation of IFI16 [interferon-γ (IFN-γ)–inducible protein 16] or its murine homolog IFI204, which are components of the cGAS/STING (stimulator of IFN genes) pathway, attenuated cytosolic DNA–induced IFN and chemokine expression in melanoma cells. PRMT5 also inhibited transcription of the gene encoding NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5), a protein that promotes the expression of genes implicated in major histocompatibility complex class I (MHCI) antigen presentation. PRMT5 knockdown augmented IFN and chemokine production and increased MHCI abundance in melanoma. Increased expression of IFI204 and NLRC5 was associated with decreased melanoma growth in murine models, and increased expression of IFI16 and NLRC5 correlated with prolonged survival of patients with melanoma. Combination of pharmacological (GSK3326595) or genetic (shRNA) inhibition of PRMT5 with immune checkpoint therapy limited growth of murine melanoma tumors (B16F10 and YUMM1.7) and enhanced therapeutic efficacy, compared with the effect of either treatment alone. Overall, our findings provide a rationale to test PRMT5 inhibitors in immunotherapy-based clinical trials as a means to enhance an antitumor immune response.

蛋白质精氨酸甲基转移酶5（PRMT5）控制多种细胞过程，并参与癌症的发展和进程。在这里，我们报告PRMT5功能和抗肿瘤免疫力之间的负相关。PRMT5表达与人黑素瘤组织中的抗肿瘤免疫基因签名有关。降低PRMT5活性可拮抗免疫活性但不损害免疫力的小鼠中的黑素瘤生长。IFI16 [干扰素-γ（IFN-γ）诱导蛋白16]或其鼠同源物IFI204的PRMT5甲基化，它们是cGAS / STING（干扰素基因的刺激物）途径的组成部分，减弱了胞浆DNA诱导的干扰素和趋化因子的表达黑色素瘤细胞。PRMT5还抑制编码NLRC5（包含5的核苷酸结合寡聚域样受体家族胱天蛋白酶募集结构域）的基因的转录，该蛋白可促进与主要组织相容性复合体I类（MHCI）抗原呈递有关的基因表达。PRMT5敲低增加了黑色素瘤中的IFN和趋化因子的产生，并增加了MHCI的丰度。IFI204和NLRC5在鼠模型中具有降低的黑素瘤生长相关联，且增加的表达IFI16和NLRC5用的黑色素瘤患者生存时间延长相关。与单独两种疗法的效果相比，PRMT5的药理学（GSK3326595）或遗传学（shRNA）抑制与免疫检查点疗法的组合限制了鼠类黑色素瘤肿瘤（B16F10和YUMM1.7）的生长，并增强了疗效。总体而言，我们的发现为在基于免疫疗法的临床试验中测试PRMT5抑制剂提供了依据，以此作为增强抗肿瘤免疫反应的手段。