Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer.
Loss of RBMS1 promotes anti-tumor immunity through enabling PD-L1 checkpoint blockade in triple-negative breast cancer.
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RBMS1 缺失可通过在三阴性乳腺癌中阻断 PD-L1 检查点来促进抗肿瘤免疫力
DOI：
10.1038/s41418-022-01012-0
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发表时间：
2022-11
影响因子：
12.4
通讯作者：
Wang, Yang
中科院分区：
文献类型：
--
作者：
Zhang, Jinrui;Zhang, Ge;Zhang, Wenjing;Bai, Lu;Wang, Luning;Li, Tiantian;Yan, Li;Xu, Yang;Chen, Dan;Gao, Wenting;Gao, Chuanzhou;Chen, Chaoqun;Ren, Menglin;Jiao, Yuexia;Qin, Hongqiang;Sun, Yu;Zhi, Lili;Qi, Yangfan;Zhao, Jinyao;Liu, Quentin;Liu, Han;Wang, Yang
免疫治疗已广泛应用于多种肿瘤，然而，其在治疗三阴性乳腺癌（TNBC）中的疗效仍受到挑战。同时，RNA结合蛋白在调节TNBC免疫治疗中的功能和机制在很大程度上仍然是不清楚的。在这里，我们报道了RNA结合蛋白RBMS 1在免疫冷TNBC中普遍存在。通过系统的shRNA介导的筛选，我们发现RBMS 1的缺失显著降低了TNBC中程序性死亡配体1（PD-L1）的水平。临床上，乳腺癌患者RBMS 1水平升高，且与PD-L1水平呈正相关。RBMS 1消融刺激细胞毒性T细胞介导的抗肿瘤免疫。RBMS 1调节B4 GALT 1（一种新鉴定的PD-L1糖基转移酶）的mRNA稳定性。RBMS 1的缺失使B4 GALT 1的mRNA不稳定，抑制PD-L1的糖基化，并促进PD-L1的泛素化和随后的降解。重要的是，RBMS 1耗竭与CTLA 4免疫检查点阻断或CAR-T治疗的组合增强了体外和体内的抗肿瘤T细胞免疫。总之，我们的发现通过靶向免疫抑制性RBMS 1提供了针对TNBC的新免疫策略。
Immunotherapy has been widely utilized in multiple tumors, however, its efficacy in the treatment of triple-negative breast cancers (TNBC) is still being challenged. Meanwhile, functions and mechanisms of RNA binding proteins in regulating immunotherapy for TNBC remain largely elusive. Here we reported that the RNA binding protein RBMS1 is prevalent among immune-cold TNBC. Through a systematic shRNA-mediated screen, we found depletion of RBMS1 significantly reduced the level of programmed death ligand 1 (PD-L1) in TNBC. Clinically, RBMS1 was increased in breast cancer and its level was positively correlated to that of PD-L1. RBMS1 ablation stimulated cytotoxic T cell mediated anti-tumor immunity. Mechanistically, RBMS1 regulated the mRNA stability of B4GALT1, a newly identified glycosyltransferase of PD-L1. Depletion of RBMS1 destabilized the mRNA of B4GALT1, inhibited the glycosylation of PD-L1 and promoted the ubiquitination and subsequent degradation of PD-L1. Importantly, combination of RBMS1 depletion with CTLA4 immune checkpoint blockade or CAR-T treatment enhanced anti-tumor T-cell immunity both in vitro and in vivo. Together, our findings provided a new immunotherapeutic strategy against TNBC by targeting the immunosuppressive RBMS1.
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DOI：
10.1038/nrc3239
发表时间：
2012-03-22
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Pardoll DM
通讯作者：
Pardoll DM
影响因子：
11.1
作者：
Li, Fei;Zhao, Hongfan;Tan, Wanlong
通讯作者：
Tan, Wanlong
影响因子：
50.3
作者：
Lim SO;Li CW;Xia W;Cha JH;Chan LC;Wu Y;Chang SS;Lin WC;Hsu JM;Hsu YH;Kim T;Chang WC;Hsu JL;Yamaguchi H;Ding Q;Wang Y;Yang Y;Chen CH;Sahin AA;Yu D;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
DOI：
10.1016/s0140-6736(16)00561-4
发表时间：
2016-05-07
期刊：
Lancet (London, England)
影响因子：
--
作者：
Rosenberg JE;Hoffman-Censits J;Powles T;van der Heijden MS;Balar AV;Necchi A;Dawson N;O'Donnell PH;Balmanoukian A;Loriot Y;Srinivas S;Retz MM;Grivas P;Joseph RW;Galsky MD;Fleming MT;Petrylak DP;Perez-Gracia JL;Burris HA;Castellano D;Canil C;Bellmunt J;Bajorin D;Nickles D;Bourgon R;Frampton GM;Cui N;Mariathasan S;Abidoye O;Fine GD;Dreicer R
通讯作者：
Dreicer R
DOI：
10.1073/pnas.192461099
发表时间：
2002-09-17
影响因子：
11.1
作者：
Iwai, Y;Ishida, M;Minato, N
通讯作者：
Minato, N