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Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition
Published version of a preprint
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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“EZH2 inhibition, is associated with multipronged immunomodulatory effects, encompassing immunostimulation downstream of improved antigen presentation by cancer cells”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Ennishi et al., 2019
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“01, respectively), which may further decrease the surface MHC-II levels on tumor B cells due to their role in repressing MHC-II surface expression (24, 25).”
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“BCL1 cells, which are an established model to study GC B-cell biology (28), transduced with EZH2Y641N and EZH2Y641F exhibited increased H3K27me3 levels at promoters of Nlrc5 and Ciita compared with WT EZH2 (Supplementary Fig.”
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MethodWilkinson, S. T., Vanpatten, K. A., Fernandez, D. R., Brunhoeber, P., Garsha, K. E., Glinsmann‐Gibson, B., Grogan, T. M., Teruya‐Feldstein, J., & Rimsza, L. M. (2011) · Blood · doi:10.1182/blood-2011-07-363820 · Cited by 62 · cited 12×
“However, surprisingly, MHC-II negativity by IHC was significantly correlated with unfavorable outcomes in GCB-DLBCL, whereas an opposite prognostic impact, i.e., favorable outcomes, was found in ABC-DLBCL.”
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“01, respectively), which may further decrease the surface MHC-II levels on tumor B cells due to their role in repressing MHC-II surface expression (24, 25).”
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Metadata
- 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
- Published
- 2019-04-01
- Volume
- 9
- Issue
- 4
- Pages
- 546-563
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- 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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