IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes
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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.
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- Authors
- Qiu, Z., Khalife, J., Ethiraj, P., Jaafar, C., Lin, A.-P., Holder, K. N., Ritter, J. P., Chiou, L., Huelgas-Morales, G., Aslam, S., Zhang, Z., Liu, Z., Arya, S., Gupta, Y. K., Dahia, P. L. M., & Aguiar, R. C. T.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center San Antonio, San Antonio, TX 78229, USA.
- Corresponding author
- Qiu, Zhijun
- Khalife, Jihane
- Ethiraj, Purushoth
- Jaafar, Carine
- Aguiar, Ricardo C.T.
- ORCID
- Venue
- Science Advances
- Published
- 2024-07-12
- Volume
- 10
- Issue
- 28
- Pages
- eadk2091-eadk2091
- ISSN
- 2375-2548 (ISSN-L)
- PMC
- PMC11244530
- OpenAlex
- W4400578706
- Cited by
- 25
- References
- 7
- Citations by year
- 2026: 13 · 2025: 11 · 2024: 1
- FWCI
- 7.55
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Science Advances (publishedVersion, cc-by-nc)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01BX001882, IK6 BX006542)
- Cancer Prevention and Research Institute of Texas (RP190043)
- University of Texas System
- Neuroendocrine Tumor Research Foundation
- National Institutes of Health (5r01ca102031-12)
- National Cancer Institute (P30CA054174, R01CA135332, R01CA095512, P50CA186781, R01CA264248)
- National Institute of General Medical Sciences (R01GM140456, R01GM114102, R35GM153228)
- National Institute of Allergy and Infectious Diseases (R01AI161363)
- National Institute of Environmental Health Sciences (R01ES031522)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- B-cell lymphoma, diffuse large B-cell lymphoma, immune evasion, antigen processing and presentation, MHC class II, CD74, HLA-DM, tumor microenvironment remodeling, regulatory T cells, T follicular helper cells, natural killer cells, lymphomagenesis, transcriptional regulation
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