%0 Journal Article
%T Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.
%A Chang H
%A Li M
%A Zhang L
%A Li M
%A Ong SH
%A Zhang Z
%A Zheng J
%A Xu X
%A Zhang Y
%A Wang J
%A Liu X
%A Li K
%A Luo Y
%A Wang H
%A Miao Z
%A Chen X
%A Zha J
%A Yu Y
%J Cell Oncol (Dordr)
%V 0
%N 0
%D 2024 Aug 14
%M 39141316
%F 7.051
%R 10.1007/s13402-024-00978-y
%X <B>OBJECTIVE: </B>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.<BR><B>METHODS: </B>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.<BR><B>RESULTS: </B>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.<BR><B>CONCLUSIONS: </B>The histone deubiquitinase Bap1 could be used as a biomarker for tumor stratification and as a potential therapeutic target for cancer immunotherapies.