{Reference Type}: Journal Article
{Title}: Loss of histone deubiquitinase Bap1 triggers anti-tumor immunity.
{Author}: Chang H;Li M;Zhang L;Li M;Ong SH;Zhang Z;Zheng J;Xu X;Zhang Y;Wang J;Liu X;Li K;Luo Y;Wang H;Miao Z;Chen X;Zha J;Yu Y;
{Journal}: Cell Oncol (Dordr)
{Volume}: 0
{Issue}: 0
{Year}: 2024 Aug 14
{Factor}: 7.051
{DOI}: 10.1007/s13402-024-00978-y
{Abstract}: <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.