Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.

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.