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ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade

Author

Listed:
  • Xiaolan Liu

    (Zhejiang University School of Medicine)

  • Xufeng Cen

    (Zhejiang University Medical Center)

  • Ronghai Wu

    (Hangzhou PhecdaMed Co.Ltd)

  • Ziyan Chen

    (Zhejiang University School of Medicine)

  • Yanqi Xie

    (Zhejiang University School of Medicine)

  • Fengqi Wang

    (Zhejiang University School of Medicine)

  • Bing Shan

    (Chinese Academy of Sciences)

  • Linghui Zeng

    (Hangzhou City University)

  • Jichun Zhou

    (Zhejiang University School of Medicine)

  • Bojian Xie

    (Wenzhou Medical University)

  • Yangjun Cai

    (Wenzhou Medical University)

  • Jinyan Huang

    (Zhejiang University School of Medicine)

  • Yingjiqiong Liang

    (Zhejiang University School of Medicine)

  • Youqian Wu

    (Zhejiang University School of Medicine)

  • Chao Zhang

    (Zhejiang University School of Medicine)

  • Dongrui Wang

    (Zhejiang University Medical Center)

  • Hongguang Xia

    (Zhejiang University School of Medicine
    Zhejiang University Medical Center
    Zhejiang University)

Abstract

Despite advances in cancer treatment, immune checkpoint blockade (ICB) only achieves complete response in some patients, illustrating the need to identify resistance mechanisms. Using an ICB-insensitive tumor model, here we discover cisplatin enhances the anti-tumor effect of PD-L1 blockade and upregulates the expression of Ariadne RBR E3 ubiquitin-protein ligase 1 (ARIH1) in tumors. Arih1 overexpression promotes cytotoxic T cell infiltration, inhibits tumor growth, and potentiates PD-L1 blockade. ARIH1 mediates ubiquitination and degradation of DNA-PKcs to trigger activation of the STING pathway, which is blocked by the phospho-mimetic mutant T68E/S213D of cGAS protein. Using a high-throughput drug screen, we further identify that ACY738, less cytotoxic than cisplatin, effectively upregulates ARIH1 and activates STING signaling, sensitizing tumors to PD-L1 blockade. Our findings delineate a mechanism that tumors mediate ICB resistance through the loss of ARIH1 and ARIH1-DNA-PKcs-STING signaling and indicate that activating ARIH1 is an effective strategy to improve the efficacy of cancer immunotherapy.

Suggested Citation

  • Xiaolan Liu & Xufeng Cen & Ronghai Wu & Ziyan Chen & Yanqi Xie & Fengqi Wang & Bing Shan & Linghui Zeng & Jichun Zhou & Bojian Xie & Yangjun Cai & Jinyan Huang & Yingjiqiong Liang & Youqian Wu & Chao , 2023. "ARIH1 activates STING-mediated T-cell activation and sensitizes tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39920-5
    DOI: 10.1038/s41467-023-39920-5
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    References listed on IDEAS

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    1. Simone M. Haag & Muhammet F. Gulen & Luc Reymond & Antoine Gibelin & Laurence Abrami & Alexiane Decout & Michael Heymann & F. Gisou van der Goot & Gerardo Turcatti & Rayk Behrendt & Andrea Ablasser, 2018. "Targeting STING with covalent small-molecule inhibitors," Nature, Nature, vol. 559(7713), pages 269-273, July.
    2. Janet L. Markman & Rebecca A. Porritt & Daiko Wakita & Malcolm E. Lane & Daisy Martinon & Magali Noval Rivas & Michael Luu & Edwin M. Posadas & Timothy R. Crother & Moshe Arditi, 2020. "Loss of testosterone impairs anti-tumor neutrophil function," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
    3. Tian-Chen Xiong & Ming-Cong Wei & Fang-Xu Li & Miao Shi & Hu Gan & Zhen Tang & Hong-Peng Dong & Tianzi Liuyu & Pu Gao & Bo Zhong & Zhi-Dong Zhang & Dandan Lin, 2022. "The E3 ubiquitin ligase ARIH1 promotes antiviral immunity and autoimmunity by inducing mono-ISGylation and oligomerization of cGAS," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    4. Youqian Wu & Chao Zhang & Xiaolan Liu & Zhengfu He & Bing Shan & Qingxin Zeng & Qingwei Zhao & Huaying Zhu & Hongwei Liao & Xufeng Cen & Xiaoyan Xu & Mengmeng Zhang & Tingjun Hou & Zhe Wang & Huanhuan, 2021. "ARIH1 signaling promotes anti-tumor immunity by targeting PD-L1 for proteasomal degradation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
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    1. Lien D. Nguyen & Zhiyun Wei & M. Catarina Silva & Sergio Barberán-Soler & Jiarui Zhang & Rosalia Rabinovsky & Christina R. Muratore & Jonathan M. S. Stricker & Colin Hortman & Tracy L. Young-Pearse & , 2023. "Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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