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 linked to immunostimulation that follows improved antigen presentation by cancer cells.
“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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EZH2 negatively regulates PD-L1 expression in hepatocellular carcinoma
Xiao, G., Jin, L.-L., Liu, C., Wang, Y., Meng, Y.-M., Zhou, Z., Chen, J., Yu, X.-J., Zhang, Y., Xu, J., et al. (2019) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-019-0784-9 · Cited by 182 · see citing works
Germinal center‐derived lymphomas: The darkest side of humoral immunity
Mlynarczyk, C., Fontán, L., & Melnick, A. (2019) · Immunological Reviews · doi:10.1111/imr.12755 · Cited by 179 · see citing works
The immune landscape and response to immune checkpoint blockade therapy in lymphoma
Kline, J. P., Godfrey, J. K., & Ansell, S. M. (2019) · Blood · doi:10.1182/blood.2019000847 · Cited by 163 · see citing works
Dersh, D., Phelan, J. D., Gumina, M. E., Wang, B., Arbuckle, J. H., Hollý, J., Kishton, R. J., Markowitz, T. E., Seedhom, M. O., Fridlyand, N., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.11.002 · Cited by 143 · see citing works
“It has been suggested that the use of EZH2 inhibitors to enhance APP would be limited to tumors with activating mutations (Ennishi et al., 2019).”
BackgroundResultInfluentialAdvances in targeted therapy for malignant lymphoma
Wang, L., Qin, W. D., Huo, Y., Li, X., Shi, Q., Rasko, J. E. J., Janin, A., & Zhao, W. (2020) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-020-0113-2 · Cited by 140 · see citing works
“EZH2 in GC B-cells represses the expression of a set of genes involved in terminal differentiation, such as PRDM1, IRF4, and XBP1, as well as in the negative regulation of cell-cycle progression, such as CDKN1A and CDKN1B.318–320 Mutations of EZH2 occur in 25% of FL and 21.7% of GCB-DLBCL but not in ABC-DLBCL.319,321…”
BackgroundInfluentialTargeting immune checkpoints in hematological malignancies
Salik, B., Smyth, M. J., & Nakamura, K. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00947-6 · Cited by 136 · see citing works
Nagasaki, J., Togashi, Y., Sugawara, T., Itami, M., Yamauchi, N., Yuda, J., Sugano, M., Ohara, Y., Minami, Y., Nakamae, H., et al. (2020) · Blood Advances · doi:10.1182/bloodadvances.2020002098 · Cited by 129 · see citing works
Mechanisms of resistance to immune checkpoint inhibitors
Nagasaki, J., Ishino, T., & Togashi, Y. (2022) · Cancer Science · doi:10.1111/cas.15497 · Cited by 127 · see citing works
A single-cell atlas of diffuse large B cell lymphoma
Ye, X., Wang, L., Nie, M., Wang, Y., Dong, S., Ren, W., Li, G., Li, Z., Wu, K., & Pan‐Hammarström, Q. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110713 · Cited by 112 · see citing works
Sabbatino, F., Liguori, L., Polcaro, G., Salvato, I., Caramori, G., Salzano, F. A., Casolaro, V., Stellato, C., Col, J. D., & Pepe, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21197295 · Cited by 104 · see citing works
Genomic analyses of PMBL reveal new drivers and mechanisms of sensitivity to PD-1 blockade
Chapuy, B., Stewart, C., Dunford, A. J., Kim, J., Wienand, K., Kamburov, A., Griffin, G. K., Chen, P.-H., Lako, A., Redd, R. A., et al. (2019) · Blood · doi:10.1182/blood.2019002067 · Cited by 103 · see citing works
Han, G., Deng, Q., Marques-Piubelli, M. L., Dai, E., Dang, M., Ma, M. C. J., Li, X., Yang, H., Henderson, J. M., Kudryashova, O. M., et al. (2022) · Blood Cancer Discovery · doi:10.1158/2643-3230.bcd-21-0075 · Cited by 97 · see citing works
“We not only confirmed this association at the single-cell level but also identified multiple cases of FL with CREBBP and EZH2 mutation-independent loss of MHC expression.”
BackgroundInfluentialToward a New Molecular Taxonomy of Diffuse Large B-cell Lymphoma
Ennishi, D., Hsi, E. D., Steidl, C., & Scott, D. W. (2020) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0174 · Cited by 96 · see citing works
“Genetic studies have shown recurrent alterations in GNA13 (62), TNFRSF14 (63), and chromatin-modifying genes [including EZH2 (64) and CREBBP (65)], with only a few other biologically relevant lesions identified (13, 53, 66).”
BackgroundInfluentialEZH2 abnormalities in lymphoid malignancies: underlying mechanisms and therapeutic implications
Li, B., & Chng, W. J. (2019) · Journal of Hematology & Oncology · doi:10.1186/s13045-019-0814-6 · Cited by 99 · see citing works
“In DLBCL, the survival-favoring EZH2 Y641 mutation is also a genetic mechanism underlying MHC-II deficiency, which leads to escape from immune surveillance and inferior prognosis [103].”
BackgroundGenetic mechanisms of HLA-I loss and immune escape in diffuse large B cell lymphoma
Fangazio, M., Ladewig, E., Gomez, K., Garcia‐Ibanez, L., Kumar, R., Teruya‐Feldstein, J., Rossi, D., Filip, I., Pan‐Hammarström, Q., Inghirami, G., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2104504118 · Cited by 96 · see citing works
“The B2M gene, encoding for an invariable subunit necessary for the assembly of the class I major histocompatibility complex (MHC-I), undergoes inactivating mutations and focal deletions in up to 29% of DLBCLs, constituting one of the most common altered genes in this malignancy (12, 13, 15, 16).”
InfluentialSengupta, S., Das, S., Crespo, Â. C., Cornel, A. M., Patel, A. G., Mahadevan, N. R., Campisi, M., Ali, A. K., Sharma, B., Rowe, J. H., et al. (2022) · Nature Cancer · doi:10.1038/s43018-022-00427-5 · Cited by 94 · see citing works
Turning cold tumors into hot tumors to ignite immunotherapy
Liu, Y., Wang, Y., Wang, S., Li, J., He, W. A., Fan, X.-J., & Wan, X. (2025) · Molecular Cancer · doi:10.1186/s12943-025-02477-6 · Cited by 107 · see citing works
Genetic and phenotypic attributes of splenic marginal zone lymphoma
Bonfiglio, F., Bruscaggin, A., Guidetti, F., di Bergamo, L. T., Faderl, M., Spina, V., Condoluci, A., Bonomini, L., Forestieri, G., Koch, R., et al. (2021) · Blood · doi:10.1182/blood.2021012386 · Cited by 94 · see citing works
A New Trend in Cancer Treatment: The Combination of Epigenetics and Immunotherapy
Liu, Z., Ren, Y., Weng, S., Xu, H., Li, L., & Han, X. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.809761 · Cited by 89 · see citing works
“Similar findings have been observed in lymphomas (53).”
ResultEpigenetic regulation in cancer therapy: From mechanisms to clinical advances
Tao, L., Zhou, Y., Luo, Y., Qiu, J., Xiao, Y., Zou, J., Zhang, Y., Liu, X., Yang, X., Gou, K., et al. (2024) · MedComm – Oncology · doi:10.1002/mog2.59 · Cited by 93 · see citing works
Overcoming Immune Checkpoint Blockade Resistance via EZH2 Inhibition
Kim, H. J., Cantor, H., & Cosmopoulos, K. (2020) · Trends in Immunology · doi:10.1016/j.it.2020.08.010 · Cited by 87 · see citing works
Activated SUMOylation restricts MHC class I antigen presentation to confer immune evasion in cancer
Demel, U. M., Böger, M., Yousefian, S., Grunert, C., Zhang, L., Hotz, P. W., Gottschlich, A., Köse, H., Isaakidis, K., Vonficht, D., et al. (2022) · Journal of Clinical Investigation · doi:10.1172/jci152383 · Cited by 88 · see citing works
“1 μg/mL doxycycline for shaping the immunogenicity of tumor cells (26, 49).”
BackgroundZhang, Y., Wu, M., Lu, W.-C., Li, Y., Chang, C. J., & Yang, J. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2023.12.003 · Cited by 85 · see citing works
Julia, E., & Salles, G. (2021) · Future Oncology · doi:10.2217/fon-2020-1244 · Cited by 79 · see citing works
Isshiki, Y., Chen, X., Teater, M. R., Karagiannidis, I., Nam, H. S., Cai, W., Meydan, C., Xia, M., Shen, H., Gutierrez, J., et al. (2024) · Cancer Cell · doi:10.1016/j.ccell.2024.11.006 · Cited by 84 · see citing works
Cathepsin S Alterations Induce a Tumor-Promoting Immune Microenvironment in Follicular Lymphoma
Bararia, D., Hildebrand, J. A., Stolz, S., Haebe, S., Alig, S., Trevisani, C. P., Osorio‐Barrios, F., Bartoschek, M. D., Mentz, M., Pastore, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107522 · Cited by 77 · see citing works
Li, C., Wang, Y., Gong, Y., Zhang, T., Huang, J., Tan, Z. W., & Xue, L. (2021) · Clinical Epigenetics · doi:10.1186/s13148-021-01045-1 · Cited by 77 · see citing works
“Patients with relapsed/refractory DLBCL, transformed FL, other NHLs, solid tumors, and multiple myeloma (MM) were recruited in a clinical trial (NCT02082977).”
InfluentialTakahara, T., Nakamura, S., Tsuzuki, T., & Satou, A. (2023) · Cancers · doi:10.3390/cancers15030835 · Cited by 78 · see citing works
“Since EZH2 mutation is an inferior prognostic factor, EZH2 can be regarded as a therapeutic target in DLBCL [29,68].”
BackgroundInfluentialRovatti, P. E., Gambacorta, V., Lorentino, F., Ciceri, F., & Vago, L. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00147 · Cited by 73 · see citing works
“For instance, there have been several reports of HLA class II downregulation in lymphoma cells as a consequence of deletions and point mutations of HLA class II genes and their regulators, including CIITA (44, 45).”
BackgroundInfluentialSheng, W., Liu, Y., Chakraborty, D., Debo, B. M., & Shi, Y. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-20-0017 · Cited by 70 · see citing works
“Thus, inhibition of PRC2 has been reported to restore anti-tumor immunity in MHC-I-low tumor models (3, 4).”
BackgroundMHC Class I Deficiency in Solid Tumors and Therapeutic Strategies to Overcome It
Shklovskaya, E., & Rizos, H. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22136741 · Cited by 67 · see citing works
“Other epigenetic mechanisms suppress MHC-I expression in cancer, such as DNA hypermethylation at the promoters of MHC-I heavy chains/antigen-presenting machinery (APM) genes, and trimethylation of lysine 27 on histone 3 (H3K27me3 repressive mark) by the Polycomb Repressive Complex 2 (PRC2) [43,44].”
BackgroundInfluentialMondello, P., Famà, A., Larson, M. C., Feldman, A. L., Villasboas, J. C., Yang, Z.-Z., Galkin, I., Svelolkin, V., Postovalova, E., Bagaev, A., et al. (2021) · Blood Cancer Journal · doi:10.1038/s41408-021-00521-4 · Cited by 66 · see citing works
EZH1/EZH2 inhibition enhances adoptive T cell immunotherapy against multiple cancer models
Porazzi, P., Nason, S., Yang, Z., Carturan, A., Ghilardi, G., Guruprasad, P., Patel, R. P., Tan, M. T., Padmanabhan, A. A., Lemoine, J., et al. (2025) · Cancer Cell · doi:10.1016/j.ccell.2025.01.013 · Cited by 65 · see citing works
Histone methylation antagonism drives tumor immune evasion in squamous cell carcinomas
Li, Y., Goldberg, E. M., Chen, X., Xu, X., McGuire, J. T., Leuzzi, G., Karagiannis, D., Tate, T., Farhangdoost, N., Horth, C., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.09.007 · Cited by 64 · see citing works
New strategies in soft tissue sarcoma treatment
Ceruso, M. S., El-Ghazzi, N., & Italiano, A. (2024) · Journal of Hematology & Oncology · doi:10.1186/s13045-024-01580-3 · Cited by 68 · see citing works
“Preclinical models have highlighted the role of EZH2 in immunomodulation [58], and synergies between EZH2 inhibition and ICI efficacy have been demonstrated in various types of solid tumors [59, 60].”
BackgroundGambacorta, V., Beretta, S., Ciccimarra, M., Zito, L., Giannetti, K., Andrisani, A., Gnani, D., Zanotti, L., Oliveira, G., Carrabba, M. G., et al. (2022) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0980 · Cited by 62 · see citing works
“Specifically, the catalytic subunit of PRC2, EZH2, has emerged as a potent regulator of antigen presentation in genome-wide screenings (18, 19), its mutations have been associated with impaired HLA expression in diffuse large B-cell lymphomas (17), and overexpression of PRC2 in solid tumors has been shown to drive the…”
BackgroundCao, Z., Shi, X., Tian, F., Yu, F., Wu, B. J., Mrđenović, S., Nian, X., Ji, J., Xu, H., Chen, K., et al. (2021) · Cell Death and Disease · doi:10.1038/s41419-020-03354-4 · Cited by 60 · see citing works
“No blind method was applied in the research and random number method was applied to randomly divide all mice into the following six groups (n= 6 mice per group): (1) PC3 cell line+ negative control siRNA, (2) PC3 cell line + KDM6B siRNA, (3) C42B cell line+ negative control siRNA, (4) C42B cell line+ KDM6B siRNA, (5)…”
Immune-Checkpoint Inhibitors in B-Cell Lymphoma
Armengol, M., Santos, J. C., Fernández-Serrano, M., Profitós-Pelejà, N., Ribeiro, M. L., & Roué, G. (2021) · Cancers · doi:10.3390/cancers13020214 · Cited by 57 · see citing works
The alternative RelB NF-κB subunit is a novel critical player in diffuse large B-cell lymphoma
Eluard, B., Nuan-Aliman, S., Faumont, N., Collares, D., Bordereaux, D., Montagne, A., Martins, I., Cagnard, N., Caly, M., Taoui, O., et al. (2021) · Blood · doi:10.1182/blood.2020010039 · Cited by 57 · see citing works
Cerchietti, L. C. A. (2024) · Blood · doi:10.1182/blood.2023021002 · Cited by 60 · see citing works
Autio, M. I., Leivonen, S., Brück, O. E., Karjalainen‐Lindsberg, M., Pellinen, T. S., & Leppä, S. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-21-3140 · Cited by 57 · see citing works
Pharmacological targeting of the cancer epigenome
Mabe, N. W., Perry, J. A., Malone, C. F., & Stegmaier, K. (2024) · Nature Cancer · doi:10.1038/s43018-024-00777-2 · Cited by 58 · see citing works
“EZH2 inhibitors have also been found to sensitize lung cancer to standard chemotherapy 212 or to promote increased expression of tumor cell antigens such as GD2 194,213,214 or increased MHC expression 207,215 .”
Balasubramanian, A., John, T., & Asselin-Labat, M.-L. (2022) · Biochemical Society Transactions · doi:10.1042/bst20210961 · Cited by 56 · see citing works
Roschewski, M. J., Phelan, J. D., & Wilson, W. H. (2020) · The Cancer Journal · doi:10.1097/ppo.0000000000000450 · Cited by 55 · see citing works
Shah, S. B., Carlson, C. R., Lai, K., Zhong, Z., Marsico, G., Lee, K. M., Vélez, N. E. F., Abeles, E. B., Allam, M., Hu, T., et al. (2023) · Nature Materials · doi:10.1038/s41563-023-01495-3 · Cited by 52 · see citing works
Chan, K. L., Gomez, J., Cardinez, C., Kumari, N., Sparbier, C. E., Lam, E. Y. N., Yeung, M. M., Garciaz, S., Kuzich, J. A., Ong, D. M., et al. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.09.007 · Cited by 52 · see citing works
Grabek, J., Straube, J., Bywater, M. J., & Lane, S. (2020) · Cells · doi:10.3390/cells9081901 · Cited by 54 · see citing works
“Commitment of HSCs or MPPs to specific lineages requires the removal of the H3K27me3 mark at the loci of master transcription factor regulators of lineage [95,96].”
BackgroundImmunotherapy for SMARCB1-Deficient Sarcomas: Current Evidence and Future Developments
Ngo, C., & Postel-Vinay, S. C. (2022) · Biomedicines · doi:10.3390/biomedicines10030650 · Cited by 52 · see citing works
“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…”
BackgroundGuo, W., Wang, Y., Yang, M., Wang, Z., Wang, Y., Chaurasia, S., Wu, Z., Zhang, M., Yadav, G. S., Rathod, S., et al. (2021) · Science Advances · doi:10.1126/sciadv.abb3555 · Cited by 50 · see citing works
Alame, M., Cornillot, E., Cacheux, V., Rigau, V., Costes‐Martineau, V., Szablewski, V., & Colinge, J. (2021) · Theranostics · doi:10.7150/thno.54343 · Cited by 50 · see citing works
“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 · see citing works
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 48 · see citing works
Hoffmann, F., Niebel, D., Aymans, P., Ferring‐Schmitt, S., Dietrich, D., & Landsberg, J. (2020) · Clinical Epigenetics · doi:10.1186/s13148-020-0818-7 · Cited by 48 · see citing works
Resistance to immune checkpoint inhibitors and the tumor microenvironment
Kawashima, S., & Togashi, Y. (2022) · Experimental Dermatology · doi:10.1111/exd.14716 · Cited by 49 · see citing works
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 · see citing works
Targeting epigenetics in sarcomas through EZH2 inhibition
Italiano, A. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00868-4 · Cited by 46 · see citing works
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 · see citing works
Wang, Z., Han, M., Wang, Y., Wang, N., Yang, Y., Shao, B., Miao, Q., Shi, Z., Yan, F., & Feng, S. (2025) · ACS Nano · doi:10.1021/acsnano.4c15761 · Cited by 42 · see citing works
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 41 · see citing works
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 · see citing works
Mulder, T. A., Wahlin, B. E., Österborg, A., & Palma, M. (2019) · Cancers · doi:10.3390/cancers11070915 · Cited by 40 · see citing works
“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 · see citing works
“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 · see citing works
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 41 · see citing works
“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 38 · see citing works
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 40 · see citing works
“[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 39 · see citing works
“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].”
BackgroundBao, Y., Qiao, Y., Choi, J. E., Zhang, Y., Mannan, R., Cheng, C., He, T., Zheng, Y., Yu, J., Gondal, M. N., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2314416120 · Cited by 39 · see citing works
“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 · see citing works
Tazemetostat for Advanced Epithelioid Sarcoma: Current Status and Future Perspectives
Simeone, N., Frezza, A. M., Zaffaroni, N., & Stacchiotti, S. (2020) · Future Oncology · doi:10.2217/fon-2020-0781 · Cited by 38 · see citing works
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 38 · see citing works
Guo, B., Tan, X., & Cen, H. (2020) · PLoS ONE · doi:10.1371/journal.pone.0242191 · Cited by 37 · see citing works
“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 · see citing works
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 · see citing works
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 34 · see citing works
“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 · see citing works
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 · see citing works
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 32 · see citing works
“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 34 · see citing works
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 33 · see citing works
“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
- 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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