1. IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes.
- Author
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Qiu Z, Khalife J, Ethiraj P, Jaafar C, Lin AP, Holder KN, Ritter JP, Chiou L, Huelgas-Morales G, Aslam S, Zhang Z, Liu Z, Arya S, Gupta YK, Dahia PLM, and Aguiar RCT
- Subjects
- Animals, Humans, Mice, Lymphoma, B-Cell genetics, Lymphoma, B-Cell immunology, Tumor Microenvironment immunology, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse immunology, Lymphoma, Large B-Cell, Diffuse pathology, Cell Line, Tumor, Tumor Escape genetics, Gene Expression Regulation, Neoplastic, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Antigen Presentation immunology, Antigen Presentation genetics, Mutation, Histocompatibility Antigens Class II genetics, Histocompatibility Antigens Class II immunology, Histocompatibility Antigens Class II metabolism, Antigens, Differentiation, B-Lymphocyte genetics, Antigens, Differentiation, B-Lymphocyte metabolism
- Abstract
The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells, increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.
- Published
- 2024
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