Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response
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.
Authors
- Yuqi Huang (ORCID: https://orcid.org/0000-0002-3060-8418)
- Kun Xiang (ORCID: https://orcid.org/0000-0001-7793-4352)
- Tao Yin (ORCID: https://orcid.org/0000-0001-5295-3645)
- De Huang (ORCID: https://orcid.org/0009-0000-6781-9932)
- Yi Ding (ORCID: https://orcid.org/0000-0002-2158-3108)
- Handan Xiang (ORCID: https://orcid.org/0000-0001-7957-7336)
- Yaosi Liang (ORCID: https://orcid.org/0000-0002-3478-0864)
- Bryan Jian Wei Lim (ORCID: https://orcid.org/0000-0002-6048-2609)
- Liuyang Wang (ORCID: https://orcid.org/0000-0001-9556-2361)
- Xiao‐Fan Wang (ORCID: https://orcid.org/0000-0001-7875-3940)
- Qi-Jing Li (ORCID: https://orcid.org/0000-0002-0542-9784)
- Minjia Tan (ORCID: https://orcid.org/0000-0002-6784-9653)
- Guoping Wang (ORCID: https://orcid.org/0000-0002-9166-8596)
- Chengsong Yan
- Peter B. Alexander
- Junying Chen (ORCID: https://orcid.org/0000-0001-5150-5736)
- Ergang Wang (ORCID: https://orcid.org/0000-0003-2550-3686)
- Lianmei Tan (ORCID: https://orcid.org/0000-0002-1445-4375)
- Poorva Mudgal
- Zhehao Ma
Institutions
- Agency for Science, Technology and Research (SG)
- Duke University (US)
- Chinese Academy of Sciences (CN)
- Singapore Immunology Network (SG)
- Shanghai Institute of Materia Medica (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-10-03
- DOI
- https://doi.org/10.1038/s41467-024-52902-5
- Citations
- 14
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.37
Funders
- National Research Foundation
- Wuhan University
- National Institutes of Health
- Institute of Molecular and Cell Biology
- Biomedical Research Council
- West China Hospital, Sichuan University
- National Cancer Institute