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

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

Nature Communications

10.1038/s41467-024-52902-5

https://doi.org/10.1038/s41467-024-52902-5

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, Ergang Wang, Chengsong Yan, Zhehao Ma, Minjia Tan, Qi-Jing Li, Xiao-Fan Wang

03 October 2024

Tan, L., Yin, T., Xiang, H., Wang, L., Mudgal, P., Chen, J., Ding, Y., Wang, G., Lim, B. J. W., Huang, Y., Huang, D., Liang, Y., Alexander, P. B., Xiang, K., Wang, E., Yan, C., Ma, Z., Tan, M., Li, Q.-J., & Wang, X.-F. (2024). Aberrant cytoplasmic expression of UHRF1 restrains the MHC-I-mediated anti-tumor immune response. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-52902-5

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.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

This research / project is supported by the National Research Foundation, Singapore - NRF Investigatorship
Grant Reference no. : NRF-NRFI09-0009

This research is supported by core funding from: Biomedical Research Council
Grant Reference no. :

https://oar.a-star.edu.sg/communities-collections/articles/21583

2041-1723

Institute of Molecular & Cell Biology

https://www.nature.com/articles/s41467-024-52902-5.pdf