Journal Article

An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models

Tsuboyama, Natsumi, Szczepanski, Aileen, Wang, Lu, Zhang, Te, Zhao, Zibo, Beytullahoglu, Oguzhan, Luvisotto, Amanda, Tulaiha, Rima

2025

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Antigens / B cells / B-cell lymphoma / Biological response modifiers / Biomarkers / Brain cancer / BRCA1 protein / Breast cancer / Cancer / Cancer therapies / Cell culture / Cell Line, Tumor / Cell survival / Chemotherapy / CIITA protein / CRISPR / Development and progression / DNA methylation / Epigenesis, Genetic - immunology / Epigenetic inheritance / Epigenetics / Gene expression / Gene Expression Regulation, Neoplastic - immunology / Genes / Genetic aspects / Health aspects / Histocompatibility Antigens Class II - genetics / Histocompatibility Antigens Class II - immunology / Histones / Histones - genetics / Humans / Immune privilege / Immune system / Immunotherapy / Interferon / Interferon regulatory factor / Interferon regulatory factor 1 / Interferon Regulatory Factor-1 - genetics / Interferon Regulatory Factor-1 - immunology / Interferon Regulatory Factor-1 - metabolism / Lymphocytes / Lymphoma / Lymphoma, B-Cell - genetics / Lymphoma, B-Cell - immunology / Lymphoma, B-Cell - metabolism / Lymphoma, B-Cell - pathology / Major histocompatibility complex / Medical prognosis / Melanoma / Metastases / Mice / Mice, Knockout / Mutation / Non-Hodgkin's lymphomas / Nuclear Proteins - genetics / Nuclear Proteins - immunology / Nuclear Proteins - metabolism / Oncology / Oncology, Experimental / Polycomb group proteins / Proteins / Recovery of function / Signal Transduction / Stem cells / Trans-Activators - genetics / Trans-Activators - immunology / Trans-Activators - metabolism / Tumor microenvironment / Tumor suppressor genes / Tumor Suppressor Proteins - genetics / Tumor Suppressor Proteins - immunology / Tumor Suppressor Proteins - metabolism / Tumorigenesis / Tumors / Ubiquitin Thiolesterase - genetics / Ubiquitin Thiolesterase - immunology / Ubiquitin Thiolesterase - metabolism