Tumor evolution selectively inactivates the core microRNA machinery for immune evasion

Tian-Yu Song, Min Long, Hai-Xin Zhao, Miao-Wen Zou, Hong-Jie Fan, Yang Liu, Chen-Lu Geng, Min-Fang Song, Yu-Feng Liu, Jun-Yi Chen, Yu-Lin Yang, Wen-Rong Zhou, Da-Wei Huang, Bo Peng, Zhen-Gang Peng and Yong Cang ()
Additional contact information
Tian-Yu Song: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Min Long: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Hai-Xin Zhao: Oncology and Immunology Unit, WuXi Biology, WuXi AppTec (Shanghai) Co, Ltd
Miao-Wen Zou: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Hong-Jie Fan: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Yang Liu: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Chen-Lu Geng: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Min-Fang Song: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Yu-Feng Liu: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Jun-Yi Chen: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Yu-Lin Yang: Oncology and Immunology Unit, WuXi Biology, WuXi AppTec (Shanghai) Co, Ltd
Wen-Rong Zhou: Oncology and Immunology Unit, WuXi Biology, WuXi AppTec (Shanghai) Co, Ltd
Da-Wei Huang: Oncology and Immunology Unit, WuXi Biology, WuXi AppTec (Shanghai) Co, Ltd
Bo Peng: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
Zhen-Gang Peng: Oncology and Immunology Unit, WuXi Biology, WuXi AppTec (Shanghai) Co, Ltd
Yong Cang: Gene Editing Center, School of Life Science and Technology, ShanghaiTech University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-27331-3

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