An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models
There is a growing recognition of the prognostic significance associated with the expression of major histocompatibility complex (MHC) class II in tumor cells within the context of anti-cancer immunity. Mutations or homozygous deletions of MHC-II genes are frequently encountered in B-cell lymphomas that develop in immune-privileged sites, and therefore have been linked to the survival of patients with B-cell lymphoma. However, the understanding of the regulation of MHC class II expression by epigenetic and genetic factors remains incomplete. In this study, we have identified a crucial signaling pathway comprised of the histone H2AK119 deubiquitinase BAP1, the interferon regulatory factor IRF1, and the MHC-II transactivator CIITA, which directly activates the expression of MHC-II cluster genes. Disruption of the BAP1/IRF1/CIITA axis leads to a functional attenuation of MHC-II expression without affecting expression of the genes involved in cell cycle or proliferation. Notably, loss of BAP1 has no effect on B cell lymphoma cell growth in vitro while significantly accelerates tumor growth in immunocompetent mice in vivo. Indeed, by utilizing single-cell RNA-seq, a significant reduction in immune cell infiltration was observed in BAP1-depleted tumors, indicating a potential tumor suppressive function of BAP1 by regulating the tumor microenvironment and immune response. Finally, we demonstrated that pharmacological inhibition of PRC1, which deposits histone H2K119Ub and functions as an antagonist of BAP1, could rescue the MHC-II genes in BAP1 deficient B-cell lymphoma cells. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression and enhancing immunotherapy outcomes at epigenetic levels in B-cell lymphoma treatment. Overall design: To determine the function of BAP1 in transcriptional regulation in mouse B cell lymphoma cells, we depleted BAP1 by CRISPR in mouse B cell lymphoma cell line A20 and conducted ChIP-seq, RNA-seq, and ATAC-seq analysis.