Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

Cell Oncol (Dordr)

Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, 1239 Siping Road, Shanghai, 200092, China.

Published: August 2024

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Article Abstract

Purpose: Immunotherapy using PD-L1 blockade is effective in only a small group of cancer patients, and resistance is common. This emphasizes the importance of understanding the mechanisms of cancer immune evasion and resistance.

Methods: A genome-scale CRISPR-Cas9 screen identified Bap1 as a regulator of PD-L1 expression. To measure tumor size and survival, tumor cells were subcutaneously injected into both syngeneic WT mice and immunocompromised mice. The phenotypic and transcriptional characteristics of Bap1-deleted tumors were examined using flow cytometry, RNA-seq, and CUT&Tag-seq analysis.

Results: We found that loss of histone deubiquitinase Bap1 in cancer cells activates a cDC1-CD8 T cell-dependent anti-tumor immunity. The absence of Bap1 leads to an increase in genes associated with anti-tumor immune response and a decrease in genes related to immune evasion. As a result, the tumor microenvironment becomes inflamed, with more cDC1 cells and effector CD8 T cells, but fewer neutrophils and regulatory T cells. We also found that the elimination of Bap1-deleted tumors depends on the tumor MHCI molecule and Fas-mediated CD8 T cell cytotoxicity. Our analysis of TCGA data further supports these findings, showing a reverse correlation between BAP1 expression and mRNA signatures of activated DCs and T-cell cytotoxicity in various human cancers.

Conclusion: The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.

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Source
http://dx.doi.org/10.1007/s13402-024-00978-yDOI Listing

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