PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity.
PRMT5 control of cGAS/STING and NLRC5 pathways defines melanoma response to antitumor immunity.
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DOI：
10.1126/scitranslmed.aaz5683
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发表时间：
2020-07-08
影响因子：
17.1
通讯作者：
Ronai ZA
中科院分区：
文献类型：
--
作者：
Kim H;Kim H;Feng Y;Li Y;Tamiya H;Tocci S;Ronai ZA
蛋白质精氨酸甲基转移酶5（PRMT 5）控制着多种细胞过程，并与癌症的发展和进展有关。在这里，我们报告了PRMT 5功能与抗肿瘤免疫之间的负相关性。PRMT 5抑制拮抗免疫活性但非免疫受损小鼠中的黑色素瘤生长，并上调抗肿瘤免疫基因签名。IFI 16（干扰素γ诱导蛋白16）及其鼠同源物IFI 204的PRMT 5甲基化，其是cGAS（环GMP-AMP合酶）/STING（干扰素基因刺激物）途径组分，减弱了胞质-DNA诱导的干扰素和趋化因子产生。PRMT 5还抑制NLRC 5（NLR家族CARD结构域包含5）的转录，其调节与MHCI抗原呈递有关的基因。相应地，PRMT 5敲低增强干扰素和趋化因子的产生并增加MHCI表达。IFI 16/IFI 204和NLRC 5的表达升高与小鼠模型中黑色素瘤生长减少和黑色素瘤患者生存期延长相关。值得注意的是，PRMT 5的药理学（GSK 3326595）或遗传学（shRNA）抑制与免疫检查点疗法的组合限制了鼠黑素瘤肿瘤（B16 F10和YUMM1.7）的生长并增强了治疗功效。总的来说，我们的研究结果提供了在基于免疫治疗的临床试验中测试PRMT 5抑制剂作为增强抗肿瘤免疫应答的手段的基本原理。PRMT 5在黑色素瘤中的表达抑制炎症和抗原呈递，表明其抑制可以增强免疫治疗
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 inhibition antagonized melanoma growth in immunocompetent but not immunocompromised mice and upregulated an antitumor immune gene signature. PRMT5 methylation of IFI16 (interferon gamma inducible protein 16) and its murine homologue IFI204, which are cGAS (cyclic GMP-AMP synthase)/STING (stimulator of interferon genes) pathway components, attenuated cytosolic-DNA-induced interferon and chemokine production. PRMT5 also inhibited transcription of NLRC5 (NLR Family CARD Domain Containing 5), which regulates genes implicated in MHCI antigen presentation. Correspondingly, PRMT5 knockdown augmented interferon and chemokine production and increased MHCI expression. Elevated expression of IFI16/IFI204 and NLRC5 was associated with decreased melanoma growth in murine models and prolonged survival of melanoma patients. Notably, 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. Overall our findings provide a rationale to test PRMT5 inhibitors in immunotherapy-based clinical trials as a means to enhance an antitumor immune response. PRMT5 expression in melanoma suppresses inflammation and antigen presentation, suggesting its inhibition could potentiate immunotherapy
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影响因子：
16
作者：
Clarke TL;Sanchez-Bailon MP;Chiang K;Reynolds JJ;Herrero-Ruiz J;Bandeiras TM;Matias PM;Maslen SL;Skehel JM;Stewart GS;Davies CC
通讯作者：
Davies CC
影响因子：
14.9
作者：
Colaprico A;Silva TC;Olsen C;Garofano L;Cava C;Garolini D;Sabedot TS;Malta TM;Pagnotta SM;Castiglioni I;Ceccarelli M;Bontempi G;Noushmehr H
通讯作者：
Noushmehr H
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
DOI：
10.4049/jimmunol.1200064
发表时间：
2012-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Biswas A;Meissner TB;Kawai T;Kobayashi KS
通讯作者：
Kobayashi KS
影响因子：
5.8
作者：
Gu, Zuguang;Eils, Roland;Schlesner, Matthias
通讯作者：
Schlesner, Matthias