Tumor evolution selectively inactivates the core microRNA machinery for immune evasion.
Tumor evolution selectively inactivates the core microRNA machinery for immune evasion.
复制标题
肿瘤进化选择性地使核心微小RNA机制失活以实现免疫逃逸。
DOI：
10.1038/s41467-021-27331-3
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发表时间：
2021-12-01
影响因子：
16.6
通讯作者：
Cang Y
中科院分区：
文献类型：
--
作者：
Song TY;Long M;Zhao HX;Zou MW;Fan HJ;Liu Y;Geng CL;Song MF;Liu YF;Chen JY;Yang YL;Zhou WR;Huang DW;Peng B;Peng ZG;Cang Y
癌细胞获得遗传异质性以逃避肿瘤演变过程中的免疫监视，但缺乏区分驱动突变和乘客突变的系统方法。在这里，我们研究了不同的免疫压力对肿瘤克隆动力学和免疫逃避机制的影响，通过在同基因小鼠肿瘤模型和共培养系统中结合免疫编辑肿瘤的大规模平行测序和CRISPR文库筛选。我们发现，核心microRNA（miRNA）生物发生和靶向机制维持了癌细胞对PD-1非依赖性T细胞介导的细胞毒性的敏感性。机制的遗传失活或ANKRD 52频繁患者突变的重新引入抑制了癌细胞中的JAK-STAT-干扰素-γ信号传导和抗原呈递，主要是通过消除细胞因子信号传导抑制因子1（SOCS 1）的miR-155靶向沉默。在几乎所有人类癌症类型中，每种miRNA机制组分的表达与肿瘤内T细胞浸润密切相关。我们的数据表明，癌细胞可以利用进化上保守的miRNA途径来逃避T细胞介导的消除和免疫治疗。microRNA机制的失调在癌症发展中起着关键作用。在这里，作者表明，参与microRNA介导的基因沉默的蛋白质（如ANKRD 52或AGO 2）的失活，在临床前癌症模型中赋予了对T细胞介导的免疫应答的抗性。
Cancer cells acquire genetic heterogeneity to escape from immune surveillance during tumor evolution, but a systematic approach to distinguish driver from passenger mutations is lacking. Here we investigate the impact of different immune pressure on tumor clonal dynamics and immune evasion mechanism, by combining massive parallel sequencing of immune edited tumors and CRISPR library screens in syngeneic mouse tumor model and co-culture system. We find that the core microRNA (miRNA) biogenesis and targeting machinery maintains the sensitivity of cancer cells to PD-1-independent T cell-mediated cytotoxicity. Genetic inactivation of the machinery or re-introduction of ANKRD52 frequent patient mutations dampens the JAK-STAT-interferon-γ signaling and antigen presentation in cancer cells, largely by abolishing miR-155-targeted silencing of suppressor of cytokine signaling 1 (SOCS1). Expression of each miRNA machinery component strongly correlates with intratumoral T cell infiltration in nearly all human cancer types. Our data indicate that the evolutionarily conserved miRNA pathway can be exploited by cancer cells to escape from T cell-mediated elimination and immunotherapy. Dysregulation of the microRNA machinery has crucial roles in cancer development. Here the authors show that inactivation of proteins involved in microRNA-mediated gene silencing, such as ANKRD52 or AGO2, confers resistance to T cell-mediated immune response in a preclinical cancer model.
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影响因子：
64.8
作者：
Ishizuka, Jeffrey J.;Manguso, Robert T.;Haining, W. Nicholas
通讯作者：
Haining, W. Nicholas
影响因子：
64.8
作者：
Ghandi, Mahmoud;Huang, Franklin W.;Sellers, William R.
通讯作者：
Sellers, William R.
DOI：
10.1126/science.1174334
发表时间：
2009-08-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hill DA;Ivanovich J;Priest JR;Gurnett CA;Dehner LP;Desruisseau D;Jarzembowski JA;Wikenheiser-Brokamp KA;Suarez BK;Whelan AJ;Williams G;Bracamontes D;Messinger Y;Goodfellow PJ
通讯作者：
Goodfellow PJ
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
影响因子：
21.3
作者：
Baer, Caroline;Squadrito, Mario Leonardo;De Palma, Michele
通讯作者：
De Palma, Michele