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

Lianmei Tan, Tao Yin, Handan Xiang, Liuyang Wang, Poorva Mudgal, Junying Chen, Yi Ding, Guoping Wang, Bryan Jian Wei Lim, Yuqi Huang, Huang De, Yaosi Liang, Peter B. Alexander, Kun Xiang, Ergang Wang, Chengsong Yan, Zhehao Ma, Minjia Tan, Qi-Jing Li () and Xiao-Fan Wang ()
Additional contact information
Lianmei Tan: Duke University School of Medicine
Tao Yin: 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
Huang De: 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
Xiao-Fan Wang: Duke University School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52902-5

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