PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade.
PRMT7 ablation stimulates anti-tumor immunity and sensitizes melanoma to immune checkpoint blockade.
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PRMT7消融术刺激抗肿瘤免疫，使黑色素瘤对免疫检查点阻断敏感。
DOI：
10.1016/j.celrep.2022.110582
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发表时间：
2022-03-29
期刊：
影响因子：
8.8
通讯作者：
Richard, Stephane
中科院分区：
文献类型：
--
作者：
Srour, Nivine;Villarreal, Oscar D.;Hardikar, Swanand;Yu, Zhenbao;Preston, Samuel;Miller, Wilson H., Jr.;Szewczyk, Magdelena M.;Barsyte-Lovejoy, Dalia;Xu, Han;Chen, Taiping;Del Rincon, Sonia, V;Richard, Stephane
尽管免疫检查点抑制剂（ICI）治疗癌症取得了成功，但耐药和复发仍很常见。联合治疗有望提高缓解率并克服这种耐药性。在本文中，我们报道了将PRMT 7抑制与ICI治疗相结合诱导了强的抗肿瘤T细胞免疫，并通过增加免疫细胞浸润来抑制体内肿瘤生长。PRMT 7缺陷型B16.F10黑色素瘤表现出干扰素途径、抗原呈递和趋化因子信号传导中的基因表达增加。在B16.F10黑色素瘤中，PRMT 7缺陷或用特异性PRMT 7抑制剂SGC 3027治疗导致DNMT表达减少，内源性逆转录病毒元件（ERV）调控区DNA甲基化丧失，以及ERV表达增加。PRMT 7缺陷细胞的RIG-I和MDA 5表达增加，其启动子处的抑制性组蛋白标记H4 R3 me 2s减少。我们的发现将PRMT 7鉴定为RIG-I、MDA 5及其ERV-dsRNA配体的表观遗传检查点，促进免疫逃逸和抗肿瘤T细胞免疫以抑制肿瘤生长。
Despite the success of immune checkpoint inhibitor (ICI) therapy for cancer, resistance and relapse are frequent. Combination therapies are expected to enhance response rates and overcome this resistance. Herein, we report that combining PRMT7 inhibition with ICI therapy induces a strong anti-tumor T cell immunity and restrains tumor growth in vivo by increasing immune cell infiltration. PRMT7 deficient B16.F10 melanoma exhibited increased expression of genes in the interferon pathway, antigen presentation and chemokine signaling. PRMT7-deficiency or treatment with SGC3027, a specific PRMT7 inhibitor, in B16.F10 melanoma resulted in reduced expression of DNMTs, loss of DNA methylation in the regulatory regions of endogenous retroviral elements (ERVs), and increased expression of ERVs. PRMT7-deficient cells had increased RIG-I and MDA5 expression with a reduction in the repressive histone mark, H4R3me2s, at their promoters. Our findings identify PRMT7 as an epigenetic checkpoint for RIG-I, MDA5 and their ERV-dsRNA ligands, facilitating immune escape and anti-tumor T cell immunity to restrain tumor growth.
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影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
8.8
作者：
Blanc, Romeo Sebastien;Vogel, Gillian;Richard, Stephane
通讯作者：
Richard, Stephane
影响因子：
10.5
作者：
Esteve, Pierre-Olivier;Chin, Hang Gyeong;Pradhan, Sriharsa
通讯作者：
Pradhan, Sriharsa
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
11.5
作者：
Feng, Yan;Roy, Amit;Weber, Jeffrey S.
通讯作者：
Weber, Jeffrey S.