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Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response
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Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response
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Journal Article
Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response
2024
Overview
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.
MHC-I mediated antigen presentation is an important element of the anti-tumour immune response. Here authors identify a tumour immune escape mechanism by which the cancer cells express the ubiquitin E3 ligase UHRF1 in the cytoplasm instead of the nuclear expression pattern observed in normal tissues, and this results in degradation of MHC-I and thus diminished antigen presentation and anti-tumour T cell response.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/109
/ 13/31
/ 14/19
/ 38/91
/ 64/60
/ 82/51
/ 82/58
/ Animals
/ Antigen Presentation - immunology
/ Antigens
/ Cancer
/ CCAAT-Enhancer-Binding Proteins - genetics
/ CCAAT-Enhancer-Binding Proteins - metabolism
/ Female
/ Gene Expression Regulation, Neoplastic
/ Histocompatibility Antigens Class I - genetics
/ Histocompatibility Antigens Class I - immunology
/ Histocompatibility Antigens Class I - metabolism
/ Humanities and Social Sciences
/ Humans
/ Immune checkpoint inhibitors
/ Immune Checkpoint Inhibitors - pharmacology
/ Immune Checkpoint Inhibitors - therapeutic use
/ Major histocompatibility complex
/ Male
/ Mice
/ Science
/ Transforming growth factor-b
/ Tumor Microenvironment - immunology
/ Tumors
/ Ubiquitin-Protein Ligases - genetics
