TY - JOUR
T1 - IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes
AU - Qiu, Zhijun
AU - Khalife, Jihane
AU - Ethiraj, Purushoth
AU - Jaafar, Carine
AU - Lin, An Ping
AU - Holder, Kenneth N.
AU - Ritter, Jacob P.
AU - Chiou, Lilly
AU - Huelgas-Morales, Gabriela
AU - Aslam, Sadia
AU - Zhang, Zhao
AU - Liu, Zhijie
AU - Arya, Shailee
AU - Gupta, Yogesh K.
AU - Dahia, Patricia L.M.
AU - Aguiar, Ricardo C.T.
N1 - Publisher Copyright:
© 2024 The Authors.
PY - 2024/7
Y1 - 2024/7
N2 - 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.
AB - 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.
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U2 - 10.1126/sciadv.adk2091
DO - 10.1126/sciadv.adk2091
M3 - Article
C2 - 38996030
AN - SCOPUS:85198610800
SN - 2375-2548
VL - 10
JO - Science Advances
JF - Science Advances
IS - 28
M1 - adk2091
ER -