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Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition
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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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“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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“In a nutshell, EZH2 inhibition can directly influence immunogenicity of cancer cells by (i): acting on the antigen presentation process: EZH2 expression contributes to the downregulation of Major Histocompatibility Complex (MHC)-I and MHC-II, which subsequently dampens the anti-tumor immune response [119,120]; (ii) ac…”
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“Sixteen HLA genes were retrieved from the literature [33] out of which 15 were found in both PCNSL cohorts in this study, i.”
MethodSingle-cell spatial analysis of tumor immune architecture in diffuse large B-cell lymphoma
Colombo, A., Hav, M., Singh, M. P., Xu, A. M., Gamboa, A., Lemos, T., Gerdtsson, E., Chen, D., Houldsworth, J., Shaknovich, R., et al. (2022) · Blood Advances · doi:10.1182/bloodadvances.2022007493 · Cited by 51
Epigenetic Therapies for Acute Myeloid Leukemia and Their Immune-Related Effects
Gambacorta, V., Gnani, D., Vago, L., & Micco, R. D. (2019) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2019.00207 · Cited by 49
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Resistance to immune checkpoint inhibitors and the tumor microenvironment
Kawashima, S., & Togashi, Y. (2022) · Experimental Dermatology · doi:10.1111/exd.14716 · Cited by 50
Biological heterogeneity in diffuse large B-cell lymphoma
Hilton, L. K., Scott, D. W., & Morin, R. D. (2023) · Seminars in Hematology · doi:10.1053/j.seminhematol.2023.11.006 · Cited by 49
Targeting epigenetics in sarcomas through EZH2 inhibition
Italiano, A. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00868-4 · Cited by 46
Chapuy, B., Wood, T., Stewart, C., Dunford, A. J., Wienand, K., Khan, S. J., Serin, N., Wang, M., Calabretta, E., Shimono, J., et al. (2024) · Blood · doi:10.1182/blood.2024025652 · Cited by 52
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Cell cross talk within the lymphoma tumor microenvironment: follicular lymphoma as a paradigm
Laurent, C., Dietrich, S., & Tarte, K. (2023) · Blood · doi:10.1182/blood.2023021000 · Cited by 47
Collective metastasis: coordinating the multicellular voyage
Wrenn, E. D., Huang, Y. C., & Cheung, K. (2021) · Clinical & Experimental Metastasis · doi:10.1007/s10585-021-10111-0 · Cited by 43
Mulder, T. A., Wahlin, B. E., Österborg, A., & Palma, M. (2019) · Cancers · doi:10.3390/cancers11070915 · Cited by 40
“MHC expression can be restored by the EZH2 inhibitor tazemetostat in vitro [70].”
BackgroundBerendsen, M. R., Stevens, W. B. C., van den Brand, M., van Krieken, J. H., & Scheijen, B. (2020) · Cancers · doi:10.3390/cancers12123553 · Cited by 40
“Alternative mechanisms that contribute to reduced MHC-I protein levels in relapsed disease involve the acquisition of gene mutations targeting (epi-)genetic regulators of MHC-I gene expression, such as EZH2 [121].”
BackgroundThe molecular mechanisms and therapeutic potential of EZH2 in breast cancer
Adibfar, S., Elveny, M., Kashikova, H. S., Mikhailova, M. V., Farhangnia, P., Vakili‐Samiani, S., Tarokhian, H., & Jadidi‐Niaragh, F. (2021) · Life Sciences · doi:10.1016/j.lfs.2021.120047 · Cited by 41
The Immunotherapy and Immunosuppressive Signaling in Therapy-Resistant Prostate Cancer
Xu, P., Wasielewski, L. J., Yang, J. C., Cai, D., Evans, C. P., Murphy, W. J., & Liu, C. (2022) · Biomedicines · doi:10.3390/biomedicines10081778 · Cited by 42
“EZH2 can negatively regulate IFN-inducible genes, immune checkpoint molecules, and major histocompatibility complex (MHC) expression [118].”
BackgroundHow metabolism bridles cytotoxic CD8+ T cells through epigenetic modifications
Acker, H. H. V., Ma, S., Scolaro, T., Kaech, S. M., & Mazzone, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.03.006 · Cited by 39
The Anticancer Potential of T Cell Receptor-Engineered T Cells
Ecsedi, M., McAfee, M. S., & Chapuis, A. G. (2020) · Trends in cancer · doi:10.1016/j.trecan.2020.09.002 · Cited by 42
“[32] Components of the proteasome complex and other proteins of the antigen processing pathway that can modulate epitope presentation[33– 35] are mostly regulated epigenetically and cell lineage-restricted, and are influenced by extrinsic factors, such as interferon-gamma (IFN-γ) signaling.[36] For example, cells of m…”
BackgroundInsights into the tumor microenvironment of B cell lymphoma
Ng, W. L., Ansell, S. M., & Mondello, P. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02579-9 · Cited by 41
“Part of the reason for an unfavorable TME may be linked to the mutation of genes directly or indirectly involved in the control of antigen presentation, including CREBBP [10], EP300 [11], EZH2 [12], and others [13].”
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“I (13, 14, 16–19).”
BackgroundTripodo, C., Zanardi, F., Iannelli, F., Mazzara, S., Vegliante, M. C., Morello, G., Napoli, A. D., Mangogna, A., Facchetti, F., Sangaletti, S., et al. (2020) · iScience · doi:10.1016/j.isci.2020.101562 · Cited by 38
Tazemetostat for Advanced Epithelioid Sarcoma: Current Status and Future Perspectives
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Pathogenesis of follicular lymphoma: genetics to the microenvironment to clinical translation
Kumar, E. A., Pickard, L., & Okosun, J. (2021) · British Journal of Haematology · doi:10.1111/bjh.17383 · Cited by 42
Guo, B., Tan, X., & Cen, H. (2020) · PLoS ONE · doi:10.1371/journal.pone.0242191 · Cited by 39
“showed a strong correlation between EHZ2 mutation enrichment and MHC class I and class II expression deficiency in diffuse large B-cell lymphoma [15].”
BackgroundCharacterization of DLBCL with a PMBL gene expression signature
Duns, G., Viganò, E., Ennishi, D., Sarkozy, C., Hung, S. S., Chavez, E. A., Takata, K., Rushton, C. K., Jiang, A., Ben‐Neriah, S., et al. (2021) · Blood · doi:10.1182/blood.2020007683 · Cited by 36
Small molecule targeting of chromatin writers in cancer
Conery, A. R., Rocnik, J. L., & Trojer, P. (2021) · Nature Chemical Biology · doi:10.1038/s41589-021-00920-5 · Cited by 36
EZH2 Inhibition Promotes Tumor Immunogenicity in Lung Squamous Cell Carcinomas
DuCote, T. J., Song, X., Naughton, K. J., Chen, F., Plaugher, D. R., Childress, A. R., Edgin, A. R., Skaggs, E. M., Qu, X., Liu, J., et al. (2024) · Cancer Research Communications · doi:10.1158/2767-9764.crc-23-0399 · Cited by 36
“Manytumorcellshaveevolvedtorepressantigen presentation machinery to evade the immune system surveillance (13).”
Epigenetic modulation of immunotherapy and implications in head and neck cancer
Zhou, L., Xu, N., Shibata, H., Saloura, V., & Uppaluri, R. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09944-0 · Cited by 36
Wang, X., Nissen, M. D., Gracias, D., Kusakabe, M., Simkin, G. O., Jiang, A., Duns, G., Sarkozy, C., Hilton, L. K., Chavez, E. A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-34408-0 · Cited by 36
Treating lymphoma is now a bit EZ-er
Morin, R. D., Arthur, S. E., & Assouline, S. E. (2021) · Blood Advances · doi:10.1182/bloodadvances.2020002773 · Cited by 34
“Similarly, reduced MHC class II is observed in a subset of DLBCLs and has been attributed to EZH2 mutations.(29) Loss of expression of MHC due to these changes contributes to immune evasion.”
BackgroundEZH2 Inhibitor Enhances the STING Agonist‒Induced Antitumor Immunity in Melanoma
Xu, T., Dai, J., Tang, L., Yang, L., Si, L., Sheng, X., Cui, C., Chi, Z., Kong, Y., & Guo, J. (2021) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2021.08.437 · Cited by 36
Sangaletti, S., Iannelli, F., Zanardi, F., Cancila, V., Portararo, P., Botti, L., Vacca, D., Chiodoni, C., Napoli, A. D., Valenti, C. F., et al. (2020) · EBioMedicine · doi:10.1016/j.ebiom.2020.103055 · Cited by 34
“This evidence adds a piece of information to the recent characterization of the genetic landscape of MHC deficiency in DLBCL [46], suggesting that a level of regulation exerted by the stromal microenvironment may intervene determining topographic biases in MHC-negativity selection.”
Result
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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