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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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BackgroundDissecting and targeting noncanonical functions of EZH2 in multiple myeloma via an EZH2 degrader
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“Furthermore, EZH2 negatively rules INF-induced genes [94,95].”
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“This study provides new theoretical support for the clinical application of Clo in solid tumors such as melanoma and lung cancer and offers new therapeutic strategies for these solid tumors.”
The future of immunotherapy for diffuse large B‐cell lymphoma
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“116 Bcl2 is a characteristic of GCB-derived, high-grade B-cell lymphomas, and studies have already reported for venetoclax in DLBCL.”
InfluentialTong, K. I., Yoon, S., Isaev, K., Bakhtiari, M., Lackraj, T., He, M. Y., Joynt, J., Silva, A., Xu, M. C., Privé, G. G., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-4027 · Cited by 24
“Efficacy in immunocompetent hosts can potentially be further enhanced through immune modulation, which could be mediated both by lenalidomide and EZH2 inhibition (54, 60).”
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Dupéré-Richer, D., Riva, A., Maji, S., Barwick, B. G., Román, H. L. C., Sobh, A., Quickstad, G., Li, J., De, U., Piper, C., et al. (2024) · Blood · doi:10.1182/blood.2024024518 · Cited by 22
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“Activating EZH2 missense mutations can also result in epigenetic downregulation of major histocompatibility complex (MHC) expression, leading to a cold or noninflamed DLBCL microenvironment.(22) We, therefore, speculated that the acquired EZH2 mutation may have resulted in pembrolizumab resistance through downregulati…”
Santasusagna, S., Zhu, S., Jawalagatti, V., Carceles-Cordon, M., Ertel, A., Garcia‐Longarte, S., Song, W., Fujiwara, N., Li, P., Mendizabal, I., et al. (2023) · Cancer Discovery · doi:10.1158/2159-8290.cd-23-0306 · Cited by 24
Treating human cancer by targeting EZH2
Xu, M., Xu, C., Wang, R., Tang, Q., Zhou, Q., Wu, W., Wan, X., Mo, H., Pan, J., & Wang, S. (2024) · Genes & Diseases · doi:10.1016/j.gendis.2024.101313 · Cited by 25
“98 Moreover, targeting EZH2 in head and neck cancer can enhance anti-tumor immunity and overcome anti-PD-1 resistance.”
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“To address this open question, we performed an integrative genomic analysis of whole-transcriptome RNA-Seq, targeted genomic sequencing, and high-resolution copy number (CN) analysis in a previously reported cohort of 347 DLBCL tumors from patients uniformly treated with R-CHOP (18, 19).”
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Duy, C., Béguelin, W., & Melnick, A. M. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a034959 · Cited by 23
“Early clinical trials (albeit in patients with aggressive disease) show that EZH2i arewell-tolerated and confer a significant clinical benefit (Gulati et al. 2018).”
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“ABC-DLBCLs have a high rate of mutations in MHC class I (MHC-I) genes [56] and low expression of MHC-II [57,58].”
Mosharaf, M. P., Reza, M. S., Göv, E., Mahumud, R. A., & Mollah, M. N. H. (2022) · Vaccines · doi:10.3390/vaccines10050771 · Cited by 20
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“The molecular mechanisms involved in these MHC-I alterations can be divided between: (a) irreversible mechanisms (“hard lesions”), including genetic changes in HLA class I heavy chains, antigen processing and presentation machinery (APM) components, or β2-microglobulin, or in other genes related to their expression; a…”
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“24,29,30 Promoter DNA methylation silences transcription of the downstream gene.”
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Combining EZH2 inhibitors with other therapies for solid tumors: more choices for better effects
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Predictive and Prognostic Molecular Factors in Diffuse Large B-Cell Lymphomas
Pileri, S. A., Tripodo, C., Melle, F., Motta, G., Tabanelli, V., Fiori, S., Vegliante, M. C., Mazzara, S., Ciavarella, S., & Derenzini, E. (2021) · Cells · doi:10.3390/cells10030675 · Cited by 18
“Intriguing research integrating transcriptomic, genetic, and immunophenotypic data of 347 DLBCLs demonstrated that MHC loss, particularly in GC-derived tumors originating from the centroblast-rich DZ, is associated with a strong enrichment of EZH2 mutations, lower T cell infiltration, and poorer outcome [47].”
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The pleiotropic roles of EZH2 in T-cell immunity and immunotherapy
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“1 3 proteins [78], and increased infiltration of T cells in the tumor microenvironment [79].”
BackgroundKoumpis, E., Papoudou‐Bai, A., Papathanasiou, K., Kolettas, E., Kanavaros, P., & Hatzimichael, E. C. (2024) · Current Issues in Molecular Biology · doi:10.3390/cimb46070420 · Cited by 17
“Several potentially effective treatment drugs that specifically target epigenetic modifiers are now being studied in patients with DLBCL [104,114].”
BackgroundSynergistic antitumor effect of combined EZH2 and DOT1L inhibition in B-cell lymphoma
Nguyen, V. T. M., Namba, H., Porter, H., Shlyueva, D., López, E., Melcher, A. A., Béguelin, W., Melnick, A. M., & Helin, K. (2025) · Blood · doi:10.1182/blood.2024026534 · Cited by 16
KRAB domain of ZFP568 disrupts TRIM28-mediated abnormal interactions in cancer cells
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“We also note that catalytically activating mutations in EZH2 (65) are significantly enriched in germinal center B-cell-like lymphoma, where EZH2 inhibitors have been shown to be clinically effective (66).”
BackgroundLou, N., Yang, M., Xie, Z., Gao, R., Zhang, L., Tang, L. M., Yao, J., Han, X., & Shi, Y. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010783 · Cited by 15
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“The impact of these alternate markers of intertumoral diversity on clinical outcomes will require larger studies; however, recent work from group has shown that MHC-II loss can identify a subset of patients whose tumors are sensitive to EZH2 inhibition (27).”
BackgroundResultAn Overview on Diffuse Large B-Cell Lymphoma Models: Towards a Functional Genomics Approach
Yanguas‐Casás, N., Pedrosa, L., Fernández‐Miranda, I., & Sánchez‐Beato, M. (2021) · Cancers · doi:10.3390/cancers13122893 · Cited by 20
EZH2 expression is associated with inferior overall survival in mantle cell lymphoma
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The correlation of EZH2 expression with the progression and prognosis of hepatocellular carcinoma
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“It reportedly also acts in immune escape via MHC class II gene suppression [32].”
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“HLA class I protein deficiencies have been reported in up to 43% of DLBCL cases.(35) We look forward to future investigations to unravel whether HLA-A mutational and protein status correlate with neoantigen profiles or the immune microenvironment of patients.”
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Mondello, P., & Ansell, S. M. (2021) · Expert Opinion on Pharmacotherapy · doi:10.1080/14656566.2021.2014815 · Cited by 15
“Accordingly, treatment with EZH2i restored expression in MHC [35] as well as CD58 [36], a costimulatory molecule critical for immune response, in EZH2 mutant cell lines.”
BackgroundAdoptive neoantigen-reactive T cell therapy: improvement strategies and current clinical researches
Huang, R., Bi, Z., Hu, S., Zhang, Q., Su, X., & Zhang, W. (2023) · Biomarker Research · doi:10.1186/s40364-023-00478-5 · Cited by 15
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Human B Lymphomas Reveal Their Secrets Through Genetic Mouse Models
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Mouse Models of Germinal Center Derived B-Cell Lymphomas
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Reiss, D. J., Nakayama, Y., Weng, A. P., Stokes, M. E., Sehn, L. H., Steidl, C., Scott, D. W., Huang, C. C., & Gandhi, A. K. (2024) · Leukemia · doi:10.1038/s41375-024-02239-1 · Cited by 9
An epigenetic pathway regulates MHC-II expression and function in B cell lymphoma models
Zhang, T., Beytullahoglu, O., Tulaiha, R., Luvisotto, A., Szczepanski, A. P., Tsuboyama, N., Zhao, Z., & Wang, L. (2025) · Journal of Clinical Investigation · doi:10.1172/jci179703 · Cited by 11
“Next, we sought to determine whether the increased tumor growth ability is due to the loss of MHC-II molecules in BAP1-defi-Figure proteins such as EZH2 (49), the enzymatic subunit within PRC2.”
InfluentialEngaging the Innate and Adaptive Antitumor Immune Response in Lymphoma
Csizmar, C. M., & Ansell, S. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22073302 · Cited by 13
Pickard, L., Palladino, G., & Okosun, J. (2020) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2020.1762883 · Cited by 14
Jin, M. C., Connolly, I. D., Ravi, K., Tobert, D. G., MacDonald, S. M., & Shin, J. H. (2024) · Neurosurgical FOCUS · doi:10.3171/2024.2.focus2417 · Cited by 10
The epigenetic role of EZH2 in acute myeloid leukemia
Fang, J., Zhang, J., Zhu, L., Xin, X., & Hu, H. (2024) · PeerJ · doi:10.7717/peerj.18656 · Cited by 10
“In addition, PRC2/EZH2 is known to regulate the expression of HLA and other immune-related molecules in solid tumors and lymphomas, thus underscoring its role as a potent regulator of antigen presentation ( Burr et al., 2019 ; Dersh et al., 2021 ; Ennishi et al., 2019 ).”
Clinical Applications of Genomic Alterations in ATLL: Predictive Markers and Therapeutic Targets
Yoshida, N., Miyoshi, H., & Ohshima, K. (2021) · Cancers · doi:10.3390/cancers13081801 · Cited by 10
“An immunomodulatory agent, lenalidomide, has been reported to target IRF4 in DLBCL and multiple myeloma [25,86].”
BackgroundInfluentialProteomics Identifies Circulating TIMP-1 as a Prognostic Biomarker for Diffuse Large B-Cell Lymphoma
Lou, N., Wang, G., Wang, Y., Xu, M., Zhou, Y. L., Tan, Q., Zhong, Q., Zhang, L., Zhang, X., Liu, S., et al. (2023) · Molecular & Cellular Proteomics · doi:10.1016/j.mcpro.2023.100625 · Cited by 10
Eriksen, P. R. G., de Groot, F. A., Clasen‐Linde, E., Brown, P. D. N., de Groen, R. A. L., Melchior, L., Maier, A. D., Minderman, M., Vermaat, J. S. P., von Buchwald, C., et al. (2024) · Blood Advances · doi:10.1182/bloodadvances.2023011517 · Cited by 11
“55,56 In addition to HLA loss, we addressed the possible activation of the PD-1/PD-L1 immune checkpoint, which suppresses T-cell activity in the tumor microenvironment of various hematological malignancies such as Hodgkin lymphoma and primary mediastinal BCL. 41 58-60 Furthermore, a phase 2…”
BackgroundThe Biological Basis of Histologic Transformation
Kumar, E. A., Okosun, J., & Fitzgibbon, J. (2020) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2020.02.010 · Cited by 10
The Premalignant Ancestor Cell of t(14;18)+ Lymphoma
Brisou, G., Nadel, B., & Roulland, S. (2021) · HemaSphere · doi:10.1097/hs9.0000000000000579 · Cited by 10
Patel, N. A., Slack, G. W., Bodo, J., Ben‐Neriah, S., Villa, D. R., Durkin, L. M., Socha, D. S., Steidl, C., & Hsi, E. D. (2021) · American Journal of Clinical Pathology · doi:10.1093/ajcp/aqab154 · Cited by 10
Epigenetic Modifications in Lymphoma and Their Role in the Classification of Lymphomas
Harrop, S., Yannakou, C. K., van der Weyden, C., & Prince, H. M. (2022) · Hemato · doi:10.3390/hemato3010015 · Cited by 9
“The implications of the resultant histone modifications for lymphomagenesis are yet to be fully understood but suggest a state of transcriptional repression [6,14,15].”
BackgroundLi, Z., Duan, Y., Ke, Q., Wang, M., Cen, H., & Zhu, X. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.1000460 · Cited by 9
The POD24 challenge: where do we go from here for early progressors?
Mondello, P., & Casulo, C. (2024) · Hematology · doi:10.1182/hematology.2024000662 · Cited by 9
Peng, L., Zhao, W., Yin, T., Xu, C., Wang, G., & Du, M. (2023) · Journal of Reproductive Immunology · doi:10.1016/j.jri.2023.103980 · Cited by 11
Kwantwi, L. B. (2023) · Clinical and Experimental Medicine · doi:10.1007/s10238-023-01240-9 · Cited by 10
Chen, L., Ruan, J., Chen, Y., Deng, W., Lai, J., Fan, L., Cai, J., Ding, C., Lin, Q., Xiang, B., et al. (2023) · Frontiers in Veterinary Science · doi:10.3389/fvets.2023.1167444 · Cited by 9
“EZH2 is the catalytic subunit of polycomb repressive complex 2 and plays a crucial role in many physiological or pathological activities, including the immune response (32).”
BackgroundLiu, B., Duan, X., Wang, G., Tang, Y., Zhou, K., Zhang, J. Q., Yu, Y., & Zhang, H. (2026) · Science Advances · doi:10.1126/sciadv.aea9892 · Cited by 8
“Tumors with enhanced EZH2 activity or stability frequently display immunosuppressive tumor microenvironments and are often resistant to immuno-therapy ( 23 , 24 ).”
Hu, Y., Zhang, X., Li, Q., Zhou, Q., Fang, D., & Lu, Y.-Y. (2023) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2023.09.030 · Cited by 8
“EZH2 promotes anticancer immune responses by regulating Th1 chemokine expression, myeloid-derived suppressor cells, or CD8 T cell infiltration [40,41].”
BackgroundUnraveling MCL biology to understand resistance and identify vulnerabilities
Sarkozy, C., Tessoulin, B., & Chiron, D. (2024) · Blood · doi:10.1182/blood.2023022351 · Cited by 9
Harnessing lymphoma epigenetics to improve therapies (article not eligible for CME credit)
Yang, H., & Green, M. R. (2020) · Hematology · doi:10.1182/hematology.2020006908 · Cited by 8
Can we use epigenetics to prime chemoresistant lymphomas?
Amengual, J. E. (2020) · Hematology · doi:10.1182/hematology.2020000092 · Cited by 8
Biology in Practice: Harnessing the Curative Potential of the Immune System in Lymphoid Cancers
Aoki, T., Savage, K. J. J., & Steidl, C. (2021) · Journal of Clinical Oncology · doi:10.1200/jco.20.01761 · Cited by 7
Harnessing lymphoma epigenetics to improve therapies
Yang, H., & Green, M. R. (2020) · Blood · doi:10.1182/blood.2020006908 · Cited by 8
Targeting EZH2 Increases Therapeutic Efficacy of Check-Point Blockade in Models of Prostate CancerPreprint
Sheahan, A. V., Morel, K. L., Burkhart, D. L., Baca, S. C., Labbé, D. P., Roehle, K., Heckler, M., Calagua, C., Ye, H., Galbo, P. M., et al. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/730135 · Cited by 8
“EZH2 can negatively regulate interferon (IFN) response genes, Th-1 type chemokines, and MHC expression in multiple tumor cell types (5, 6).”
BackgroundCao, L., Tang, D., Yu, Z., Shen, Y., Wang, Y., Li, Y., Chen, J., Liu, Z., Yin, J., Xiao, H., et al. (2024) · Advanced Functional Materials · doi:10.1002/adfm.202403225 · Cited by 7
The mutational profile of immune surveillance genes in diagnostic and refractory/relapsed DLBCLs
Nesic, M., Sønderkær, M., Brøndum, R. F., El‐Galaly, T. C., Pedersen, I. S., Bøgsted, M., & Dybkær, K. (2021) · BMC Cancer · doi:10.1186/s12885-021-08556-3 · Cited by 7
“In dDLBCL, loss of expression of MHC class I and II molecules frequently occurs, 40–60% and 20–40%, respectively, while the concurrent loss of both molecules is observed in approximately 20% of cases [17, 18].”
BackgroundZhang, C., Wang, L., Xu, C., Xu, H., & Wu, Y. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1079924 · Cited by 9
“EZH2 inhibitors can significantly restore HLA expression in EZH2mutated human DLBCL cell lines, suggesting that complementary therapeutic approaches combining ICIs with epigenetic reprogramming may reverse the resistance to ICIs (Ennishi et al., 2019).”
BackgroundImmunomodulatory Agents in Follicular Lymphoma
Ysebaert, L., & Morschhauser, F. (2020) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2020.02.007 · Cited by 7
Mouse Models in the Study of Mature B-Cell MalignanciesPreprint
Pasqualucci, L., & Klein, U. (2020) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a034827 · Cited by 8
Bosch‐Schips, J., Parisi, X., Climent, F., & Vega, F. (2024) · Human Pathology · doi:10.1016/j.humpath.2024.105676 · Cited by 6
Kobayashi, H., Chijimatsu, R., Naoi, Y., Otani, Y., Mizuta, R., Fujii, K., Ishida, J., Murakami, H., Ujiie, H., Ikeuchi, K., et al. (2024) · Blood Neoplasia · doi:10.1016/j.bneo.2024.100058 · Cited by 6
“Notably, in systemic DLBCL, the tumor B-cell GC states in fl uence prognosis, which has been attributed to differences in the major histocompatibility complex class 2 expression levels and the immune microenvironment, 10-12 underscoring the pivotal role of GC states in systemic DLBCL.”
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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