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Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response

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Listed:
  • Lianmei Tan

    (Duke University School of Medicine)

  • Tao Yin

    (Duke University School of Medicine
    Duke University School of Medicine)

  • Handan Xiang

    (Duke University School of Medicine)

  • Liuyang Wang

    (Duke University School of Medicine)

  • Poorva Mudgal

    (TCRCure Biopharma)

  • Junying Chen

    (Duke University School of Medicine)

  • Yi Ding

    (Duke University School of Medicine)

  • Guoping Wang

    (Duke University School of Medicine)

  • Bryan Jian Wei Lim

    (Duke University School of Medicine)

  • Yuqi Huang

    (Chinese Academy of Sciences)

  • De Huang

    (Duke University School of Medicine)

  • Yaosi Liang

    (Duke University School of Medicine)

  • Peter B. Alexander

    (Duke University School of Medicine)

  • Kun Xiang

    (Duke University School of Medicine)

  • Ergang Wang

    (Duke University School of Medicine)

  • Chengsong Yan

    (Duke University School of Medicine)

  • Zhehao Ma

    (Duke University School of Medicine)

  • Minjia Tan

    (Chinese Academy of Sciences)

  • Qi-Jing Li

    (Duke University School of Medicine
    Agency for Science, Technology and Research (A*STAR)
    Agency for Science, Technology and Research (A*STAR))

  • Xiao-Fan Wang

    (Duke University School of Medicine)

Abstract

Immunotherapy successfully complements traditional cancer treatment. However, primary and acquired resistance might limit efficacy. Reduced antigen presentation by MHC-I has been identified as potential resistance factor. Here we show that the epigenetic regulator ubiquitin-like with PHD and ring finger domains 1 (UHRF1), exhibits altered expression and aberrant cytosolic localization in cancerous tissues, where it promotes MHC-I ubiquitination and degradation. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the tumor microenvironment (TME), such as TGF-β, enabling UHRF1 to bind MHC-I. Downregulation of MHC-I results in suppression of the antigen presentation pathway to establish an immune hostile TME. UHRF1 inactivation by genetic deletion synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumour memory response by evoking low-affinity T cells. Our study adds to the understanding of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.

Suggested Citation

  • Lianmei Tan & Tao Yin & Handan Xiang & Liuyang Wang & Poorva Mudgal & Junying Chen & Yi Ding & Guoping Wang & Bryan Jian Wei Lim & Yuqi Huang & De Huang & Yaosi Liang & Peter B. Alexander & Kun Xiang , 2024. "Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52902-5
    DOI: 10.1038/s41467-024-52902-5
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