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Tumor evolution selectively inactivates the core microRNA machinery for immune evasion
Nature Communications ( IF 14.7 ) Pub Date : 2021-12-01 , DOI: 10.1038/s41467-021-27331-3
Tian-Yu Song 1, 2, 3 , Min Long 1, 3 , Hai-Xin Zhao 4 , Miao-Wen Zou 1 , Hong-Jie Fan 1, 5 , Yang Liu 1 , Chen-Lu Geng 1, 3 , Min-Fang Song 1, 2, 5 , Yu-Feng Liu 1 , Jun-Yi Chen 1 , Yu-Lin Yang 4 , Wen-Rong Zhou 4 , Da-Wei Huang 4 , Bo Peng 1 , Zhen-Gang Peng 4 , Yong Cang 1
Affiliation  

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.



中文翻译:


肿瘤进化选择性地使免疫逃避的核心 microRNA 机制失活



癌细胞在肿瘤进化过程中获得遗传异质性以逃避免疫监视,但缺乏区分驱动突变和乘客突变的系统方法。在这里,我们通过在同系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并行测序和CRISPR文库筛选,研究不同免疫压力对肿瘤克隆动态和免疫逃避机制的影响。我们发现核心 microRNA (miRNA) 生物发生和靶向机制维持癌细胞对不依赖于 PD-1 的 T 细胞介导的细胞毒性的敏感性。该机制的基因失活或重新引入ANKRD52频繁的患者突变会抑制癌细胞中的 JAK-STAT-干扰素-γ 信号传导和抗原呈递,这主要是通过废除 miR-155 靶向的细胞因子信号传导抑制因子 1 (SOCS1) 沉默来实现的。在几乎所有人类癌症类型中,每个 miRNA 机制组件的表达与瘤内 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。

更新日期:2021-12-01
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