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Tumor evolution selectively inactivates the core microRNA machinery for immune evasion

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  • Tian-Yu Song

    (Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
    Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
    Zhejiang University)

  • Min Long

    (Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
    Zhejiang 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
    University of Chinese Academy of Sciences)

  • 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
    Zhejiang University)

  • Min-Fang Song

    (Gene Editing Center, School of Life Science and Technology, ShanghaiTech University
    Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • 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)

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.

Suggested Citation

  • 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, 2021. "Tumor evolution selectively inactivates the core microRNA machinery for immune evasion," Nature Communications, Nature, vol. 12(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-27331-3
    DOI: 10.1038/s41467-021-27331-3
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