Mutations or homozygous deletions of MHC class II (MHC-II) genes are commonly found in B cell lymphomas that develop in immune-privileged sites and have been associated with patient survival. However, the mechanisms regulating MHC-II expression, particularly through genetic and epigenetic factors, are not yet fully understood. In this study, we identified a key signaling pathway involving the histone H2AK119 deubiquitinase BRCA1 associated protein 1 (BAP1), the interferon regulatory factor interferon regulatory factor 1 (IRF1), and the MHC-II transactivator class II transactivator (CIITA), which directly activates MHC-II gene expression. Disruption of the BAP1/IRF1/CIITA axis leads to a functional attenuation of MHC-II expression and MHC-II-dependent immune cell infiltration, leading to accelerated tumor growth in immunocompetent mice. Additionally, we demonstrated that pharmacological inhibition of polycomb repressive complex 1 (PRC1) - which deposits histone H2K119Ub and opposes BAP1 activity - can restore MHC-II gene expression in BAP1-deficient B cell lymphoma cells. These findings suggest that BAP1 may function as a tumor suppressor by regulating the tumor microenvironment and immune response. Our study also establishes the rationale for therapeutic strategies to restore tumor-specific MHC-II expression and enhance immunotherapy outcomes at epigenetic levels in B cell lymphoma treatment.
Keywords: Epigenetics; Oncology.