Cited by 319Lymphoma Diagnosis and TreatmentCancer Immunotherapy and BiomarkersT-cell and B-cell Immunology

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Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Ennishi, Daisuke, Takata, Katsuyoshi, Béguelin, Wendy, Duns, Gerben, Mottok, Anja, Farinha, Pedro, Bashashati, Ali, Saberi, Saeed, Boyle, Merrill, Meissner, Barbara, Ben-Neriah, Susana, Woolcock, Bruce W., Telenius, Adèle, Lai, Daniel, Teater, Matt, Kridel, Robert, Savage, Kerry J., Sehn, Laurie H., Morin, Ryan D., Marra, Marco A., Shah, Sohrab P., Connors, Joseph M., Gascoyne, Randy D., Scott, David W., Melnick, Ari M., Steidl, Christian·2019·Cancer Discovery

DOI 10.1158/2159-8290.cd-18-1090

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Abstract

Abstract We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II–deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I– and MHC-II–negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming. Significance: We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin–specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination. See related commentary by Velcheti et al., p. 472. This article is highlighted in the In This Issue feature, p. 453

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Background
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Background
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Background
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Germinal Center Dark Zone harbors ATR-dependent determinants of T-cell exclusion that are also identified in aggressive lymphomaPreprint
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The EZH2 inhibitor tazemetostat mitigates HIV immune evasion, reduces reservoir formation, and promotes durable CD8⁺ T-cell revitalizationPreprint
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Epithelioid Sarcoma
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Data from Combined EZH2 Inhibition and IKAROS Degradation Leads to Enhanced Antitumor Activity in Diffuse Large B-cell Lymphoma
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Additional file 3 of The correlation of EZH2 expression with the progression and prognosis of hepatocellular carcinoma
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“Similarly, overexpression of EZH2 RBP causes lymphoid oncogenesis by repressing the tumour suppressor genes (Ennishi et al. 2019 ).”
Additional file 1 of The correlation of EZH2 expression with the progression and prognosis of hepatocellular carcinoma
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Authors: Ennishi, D., Takata, K., Béguelin, W., Duns, G., Mottok, A., Farinha, P., Bashashati, A., Saberi, S., Boyle, M., Meissner, B., Ben-Neriah, S., Woolcock, B. W., Telenius, A., Lai, D., Teater, M., Kridel, R., Savage, K. J., Sehn, L. H., Morin, R. D., Marra, M. A., Shah, S. P., Connors, J. M., Gascoyne, R. D., Scott, D. W., Melnick, A. M., & Steidl, C.
Affiliations: 1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, British Columbia, Canada.
Weill Cornell Medicine (US)
Universität Ulm (DE)
BC Cancer Agency (CA)
Simon Fraser University (CA)
ORCID: Ennishi, Daisuke
Takata, Katsuyoshi
Béguelin, Wendy
Duns, Gerben
Mottok, Anja
Farinha, Pedro
Bashashati, Ali
Boyle, Merrill
Meissner, Barbara
Woolcock, Bruce W.
Telenius, Adèle
Lai, Daniel
Teater, Matt
Kridel, Robert
Savage, Kerry J.
Sehn, Laurie H.
Morin, Ryan D.
Marra, Marco A.
Shah, Sohrab P.
Connors, Joseph M.
Gascoyne, Randy D.
Scott, David W.
Melnick, Ari M.
Steidl, Christian
Venue: Cancer Discovery
Publisher: American Association for Cancer Research (AACR)
Published: 2019-04-01
Volume: 9
Issue: 4
Pages: 546-563
ISSN: 2159-8274 (ISSN-L)
2159-8290
DOI: 10.1158/2159-8290.cd-18-1090
OpenAlex: W2912552280
Cited by: 318
References: 50
Citations by year: 2026: 24 · 2025: 33 · 2024: 51 · 2023: 45 · 2022: 46 · 2021: 58 · 2020: 46 · 2019: 15
FWCI: 30.54
Type: journal article
Language: en
Open access: closed
Locations: Cancer Discovery (publishedVersion)
PubMed (publishedVersion)
Funders: Terry Fox Research Institute (1023, 1061)
Michael Smith Foundation for Health Research Canadian Institutes of Health Research Japanese Society for The Promotion of Science.
Uehara Memorial Foundation
British Columbia Cancer Foundation
Terry Fox Research Institute Genome Canada, Genome British ColumbiaCIHR BCCF
Mildred-Scheel-Cancer-FoundationGerman Cancer Aid MSFHR
CIHR (FDN-143288)
MSFHR CIHR
Michael Smith Foundation for Health Research
Topics: Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: diffuse large B-cell lymphoma, MHC class II, EZH2 mutation, EZH2 inhibitors, tumor immune evasion, centroblastic lymphoma, tumor-infiltrating lymphocytes, epigenetic reprogramming, immunotherapy, cell of origin
MeSH terms: Enhancer of Zeste Homolog 2 Protein, Animals, Humans, Prognosis, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mice

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Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

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