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KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements

Author

Listed:
  • Shang-Min Zhang

    (Yale School of Medicine)

  • Wesley L. Cai

    (Yale School of Medicine
    University of Pittsburgh Medical Center)

  • Xiaoni Liu

    (Yale School of Medicine
    Yale School of Medicine)

  • Durga Thakral

    (Yale School of Medicine)

  • Jiesi Luo

    (Yale School of Medicine
    Yale School of Medicine)

  • Lok Hei Chan

    (Yale School of Medicine)

  • Meaghan K. McGeary

    (Yale School of Medicine
    Yale School of Medicine)

  • Eric Song

    (Yale School of Medicine)

  • Kim R. M. Blenman

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

  • Goran Micevic

    (Yale School of Medicine)

  • Shlomit Jessel

    (Yale School of Medicine)

  • Yangyi Zhang

    (Yale School of Medicine
    Xiangya Hospital, Central South University)

  • Mingzhu Yin

    (Yale School of Medicine
    Xiangya Hospital, Central South University)

  • Carmen J. Booth

    (Yale School of Medicine)

  • Lucia B. Jilaveanu

    (Yale School of Medicine
    Yale School of Medicine)

  • William Damsky

    (Yale School of Medicine
    Yale School of Medicine)

  • Mario Sznol

    (Yale School of Medicine
    Yale School of Medicine)

  • Harriet M. Kluger

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

  • Akiko Iwasaki

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    Howard Hughes Medical Institute)

  • Marcus W. Bosenberg

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

  • Qin Yan

    (Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine
    Yale School of Medicine)

Abstract

Tumours use various strategies to evade immune surveillance1,2. Immunotherapies targeting tumour immune evasion such as immune checkpoint blockade have shown considerable efficacy on multiple cancers3,4 but are ineffective for most patients due to primary or acquired resistance5–7. Recent studies showed that some epigenetic regulators suppress anti-tumour immunity2,8–12, suggesting that epigenetic therapies could boost anti-tumour immune responses and overcome resistance to current immunotherapies. Here we show that, in mouse melanoma models, depletion of KDM5B—an H3K4 demethylase that is critical for melanoma maintenance and drug resistance13–15—induces robust adaptive immune responses and enhances responses to immune checkpoint blockade. Mechanistically, KDM5B recruits the H3K9 methyltransferase SETDB1 to repress endogenous retroelements such as MMVL30 in a demethylase-independent manner. Derepression of these retroelements activates cytosolic RNA-sensing and DNA-sensing pathways and the subsequent type-I interferon response, leading to tumour rejection and induction of immune memory. Our results demonstrate that KDM5B suppresses anti-tumour immunity by epigenetic silencing of retroelements. We therefore reveal roles of KDM5B in heterochromatin regulation and immune evasion in melanoma, opening new paths for the development of KDM5B-targeting and SETDB1-targeting therapies to enhance tumour immunogenicity and overcome immunotherapy resistance.

Suggested Citation

  • Shang-Min Zhang & Wesley L. Cai & Xiaoni Liu & Durga Thakral & Jiesi Luo & Lok Hei Chan & Meaghan K. McGeary & Eric Song & Kim R. M. Blenman & Goran Micevic & Shlomit Jessel & Yangyi Zhang & Mingzhu Y, 2021. "KDM5B promotes immune evasion by recruiting SETDB1 to silence retroelements," Nature, Nature, vol. 598(7882), pages 682-687, October.
  • Handle: RePEc:nat:nature:v:598:y:2021:i:7882:d:10.1038_s41586-021-03994-2
    DOI: 10.1038/s41586-021-03994-2
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    Citations

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    Cited by:

    1. Yanan Liu & Longmiao Hu & Zhengzhen Wu & Kun Yuan & Guangliang Hong & Zhengke Lian & Juanjuan Feng & Na Li & Dali Li & Jiemin Wong & Jiekai Chen & Mingyao Liu & Jiangping He & Xiufeng Pang, 2023. "Loss of PHF8 induces a viral mimicry response by activating endogenous retrotransposons," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Wenfeng Ren & Zilong Xu & Yating Chang & Fei Ju & Hongning Wu & Zhiqi Liang & Min Zhao & Naizhen Wang & Yanhua Lin & Chenhang Xu & Shengming Chen & Yipeng Rao & Chaolong Lin & Jianxin Yang & Pingguo L, 2024. "Pharmaceutical targeting of OTUB2 sensitizes tumors to cytotoxic T cells via degradation of PD-L1," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    3. Cang Li & Zhengyu Wang & Licheng Yao & Xingyu Lin & Yongping Jian & Yujia Li & Jie Zhang & Jingwei Shao & Phuc D. Tran & James R. Hagman & Meng Cao & Yusheng Cong & Hong-yu Li & Colin R. Goding & Zhi-, 2024. "Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. Hanhan Ning & Shan Huang & Yang Lei & Renyong Zhi & Han Yan & Jiaxing Jin & Zhenyu Hu & Kaimin Guo & Jinhua Liu & Jie Yang & Zhe Liu & Yi Ba & Xin Gao & Deqing Hu, 2022. "Enhancer decommissioning by MLL4 ablation elicits dsRNA-interferon signaling and GSDMD-mediated pyroptosis to potentiate anti-tumor immunity," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    5. Tiantian Jing & Dianhui Wei & Xiaoli Xu & Chengsi Wu & Lili Yuan & Yiwen Huang & Yizhen Liu & Yanyi Jiang & Boshi Wang, 2024. "Transposable elements-mediated recruitment of KDM1A epigenetically silences HNF4A expression to promote hepatocellular carcinoma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.

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