The DOI matches its Crossref record; 41 of the 43 references it cites were found in a registry or an index.
EZH2 Inhibitor GSK126 Suppresses Antitumor Immunity by Driving Production of Myeloid-Derived Suppressor Cells
Open accessPublished version of a preprint
Abstract
Abstract Enhancer of zeste homolog (EZH2) is a key epigenetic regulator of gene expression and is frequently overexpressed in various cancer types, suggesting a role in oncogenesis. The therapeutic potential of EZH2 inhibitors is currently being explored, but their effect on antitumor immunity is largely unknown. Here we report that suppressing EZH2 activity using EZH2 inhibitor GSK126 resulted in increased numbers of myeloid-derived suppressor cells (MDSC) and fewer CD4+ and IFNγ+CD8+ T cells, which are involved in antitumor immunity. Addition of a neutralizing antibody against the myeloid differentiation antigen GR-1 or gemcitabine/5-fluorouracil–depleted MDSCs alleviated MDSC-mediated immunosuppression and increased CD4+ and CD8+ T-cell tumor infiltration and GSK126 therapeutic efficacy. Mechanistically, we identified a novel pathway of MDSC production in cancer in which EZH2 inhibition directs myeloid differentiation from primitive hematopoietic progenitor cells. These findings suggest that modulating the tumor immune microenvironment may improve the efficacy of EZH2 inhibitors. Significance: This study uncovers a potential mechanism behind disappointing results of a phase I clinical trial of EZH2 inhibitor GSK126 and identifies a translatable combinational strategy to overcome it.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“EZH2 inhibition with GSK126 reportedly favors MDSC expansion and immunosuppressive functions”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Huang et al., 2019
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Jones, P. A., & Baylin, S. B. (2007) · Cell · doi:10.1016/j.cell.2007.01.029 · Cited by 4,515
The Polycomb complex PRC2 and its mark in life
Margueron, R., & Reinberg, D. (2011) · Nature · doi:10.1038/nature09784 · Cited by 3,347
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
McCabe, M. T., Ott, H. M., Ganji, G., Korenchuk, S., Thompson, C., Van Aller, G. S., Liu, Y., Graves, A. P., III, A. D. P., Diaz, E., et al. (2012) · Nature · doi:10.1038/nature11606 · Cited by 1,786
Kleer, C. G., Cao, Q., Varambally, S., Shen, R., Ota, I., Tomlins, S. A., Ghosh, D., Sewalt, R. G. A. B., Otte, A. P., Hayes, D. F., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1933744100 · Cited by 1,649
Kim, K. H., & Roberts, C. W. M. (2016) · Nature Medicine · doi:10.1038/nm.4036 · Cited by 1,471
Vincent, J., Mignot, G., Chalmin, F., Ladoire, S., Bruchard, M., Chevriaux, A., Martin, F., Apetoh, L., Rébé, C., & Ghiringhelli, F. (2010) · Cancer Research · doi:10.1158/0008-5472.can-09-3690 · Cited by 1,245
Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy
Peng, D., Kryczek, I., Nagarsheth, N., Zhao, L., Wei, S., Wang, W., Sun, Y., Zhao, E., Vatan, L., Szeliga, W., et al. (2015) · Nature · doi:10.1038/nature15520 · Cited by 1,201
Transcriptional Heterogeneity and Lineage Commitment in Myeloid Progenitors
Paul, F., Arkin, Y., Giladi, A., Jaitin, D. A., Kenigsberg, E., Keren-Shaul, H., Winter, D., Lara-Astiaso, D., Gury, M., Weiner, A., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.013 · Cited by 1,082
EZH2 Oncogenic Activity in Castration-Resistant Prostate Cancer Cells Is Polycomb-Independent
Xu, K., Wu, Z. J., Groner, A. C., He, H. H., Cai, C., Lis, R. T., Wu, X., Stack, E. C., Loda, M. F., Liu, T., et al. (2012) · Science · doi:10.1126/science.1227604 · Cited by 901
Béguelin, W., Popovic, R., Teater, M. R., Jiang, Y., Bunting, K. L., Rosen, M., Shen, H., Yang, S. N., Wang, L., Ezponda, T., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.04.011 · Cited by 897
Kim, E. H., Kim, M., Woo, D., Shin, Y., Shin, J., Chang, N., Oh, Y. T., Kim, H., Rheey, J., Nakano, I., et al. (2013) · Cancer Cell · doi:10.1016/j.ccr.2013.04.008 · Cited by 846
Synthetic lethality by targeting EZH2 methyltransferase activity in ARID1A-mutated cancers
Bitler, B. G., Aird, K. M., Garipov, A., Li, H., Amatangelo, M. D., Kossenkov, A. V., Schultz, D., Liu, Q., Shih, I., Conejo-Garcia, J. R., et al. (2015) · Nature Medicine · doi:10.1038/nm.3799 · Cited by 684
Miranda, T. B., Cortez, C. C., Yoo, C. B., Liang, G., Abe, M., Kelly, T. K., Márquez, V. E., & Jones, P. A. (2009) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-09-0013 · Cited by 609
Chase, A., & Cross, N. C. P. (2011) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-10-2156 · Cited by 563
Terabe, M., Matsui, S., Park, J.-M., Mamura, M., Noben-Trauth, N., Donaldson, D. D., Chen, W., Wahl, S. M., Ledbetter, S. R., Pratt, B. M., et al. (2003) · The Journal of Experimental Medicine · doi:10.1084/jem.20022227 · Cited by 549
EZH2 is a potential therapeutic target for H3K27M-mutant pediatric gliomas
Mohammad, F., Weissmann, S., Leblanc, B., Pandey, D. P., Højfeldt, J. W., Comet, I., Zheng, C., Johansen, J. V., Rapin, N., Porse, B. T., et al. (2017) · Nature Medicine · doi:10.1038/nm.4293 · Cited by 535
Zhao, E., Maj, T., Kryczek, I., Li, W., Wu, K., Zhao, L., Wei, S., Crespo, J., Wan, S., Vatan, L., et al. (2016) · Nature Immunology · doi:10.1038/ni.3313 · Cited by 405
Self-citationDuPage, M., Chopra, G., Quiros, J., Rosenthal, W. L., Morar, M. M., Holohan, D., Zhang, R., Turka, L., Marson, A., & Bluestone, J. A. (2015) · Immunity · doi:10.1016/j.immuni.2015.01.007 · Cited by 332
Tumes, D. J., Onodera, A., Suzuki, A., Shinoda, K., Endo, Y., Iwamura, C., Hosokawa, H., Koseki, H., Tokoyoda, K., Suzuki, Y., et al. (2013) · Immunity · doi:10.1016/j.immuni.2013.09.012 · Cited by 291
Nagarsheth, N., Peng, D., Kryczek, I., Wu, K., Li, W., Zhao, E., Zhao, L., Wei, S., Frankel, T. L., Vatan, L., et al. (2015) · Cancer Research · doi:10.1158/0008-5472.can-15-1938 · Cited by 277
EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumours to TopoII inhibitors
Brainson, C. F., Xu, C., Desai, P. T., Berry, J. M., Rowbotham, S. P., Lin, Y.-J., Zhang, H., Márquez, V. E., Hammerman, P. S., Wong, K., et al. (2015) · Nature · doi:10.1038/nature14122 · Cited by 254
Enhancer of zeste homolog 2 (EZH2) inhibitors
Gulati, N., Béguelin, W., & Giulino-Roth, L. G. (2018) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2018.1430795 · Cited by 205
Gunawan, M., Venkatesan, N., Loh, J. T., Wong, J. F., Berger, H., Neo, W. H., Li, J. L. Y., Win, M. K. L., Yau, Y. H., Guo, T., et al. (2015) · Nature Immunology · doi:10.1038/ni.3125 · Cited by 192
van Deventer, H. W., Burgents, J. E., Wu, Q. P., Woodford, R.-M. T., Brickey, W. J., Allen, I. C., McElvania-Tekippe, E., Serody, J. S., & Ting, J. P.-Y. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-1921 · Cited by 172
Yin, J., Leavenworth, J. W., Li, Y., Luo, Q., Xie, H., Liu, X., Huang, S., Yan, H., Fu, Z., Zhang, L. Y., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521740112 · Cited by 169
EZH2 inhibition: targeting the crossroad of tumor invasion and angiogenesis
Crea, F., Fornaro, L., Bocci, G., Sun, L., Farrar, W. L., Falcone, A., & Danesi, R. (2012) · Cancer and Metastasis Reviews · doi:10.1007/s10555-012-9387-3 · Cited by 165
EZH2 is crucial for both differentiation of regulatory T cells and T effector cell expansion
Yang, X., Jiang, K., Hirahara, K., Vahedi, G., Afzali, B., Sciumè, G., Bonelli, M. M., Sun, H., Jankovic, D. L., Kanno, Y., et al. (2015) · Scientific Reports · doi:10.1038/srep10643 · Cited by 156
Kawano, M., Mabuchi, S., Matsumoto, Y., Sasano, T., Takahashi, R., Kuroda, H., Kozasa, K., Hashimoto, K., Isobe, A., Sawada, K., et al. (2015) · Scientific Reports · doi:10.1038/srep18217 · Cited by 145
He, S., Liu, Y., Meng, L., Sun, H., Wang, Y., Ji, Y., Purushe, J., Chen, P., Li, C., Madžo, J., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-02187-8 · Cited by 128
EZH2 in normal hematopoiesis and hematological malignancies
Herviou, L., Cavalli, G., Cartron, G., Klein, B., & Moreaux, J. (2015) · Oncotarget · doi:10.18632/oncotarget.6198 · Cited by 113
EZH2 promotes tumor progression via regulating VEGF-A/AKT signaling in non-small cell lung cancer
Geng, J., Li, X., Zhou, Z., et al. (2015) · Cancer Letters · doi:10.1016/j.canlet.2015.01.031 · Cited by 109
EZH2 as a potential target in cancer therapy
McCabe, M. T., & Creasy, C. L. (2014) · Epigenomics · doi:10.2217/epi.14.23 · Cited by 91
Kodach, L. L., Jacobs, R. J., Heijmans, J., van Noesel, C. J. M., Langers, A. M. J., Verspaget, H. W., Hommes, D. W., Offerhaus, G. J. A., van den Brink, G. R., & Hardwick, J. C. H. (2010) · Carcinogenesis · doi:10.1093/carcin/bgq147 · Cited by 83
Regulation of T Cell Differentiation and Function by EZH2
Karantanos, T., Chistofides, A., Barhdan, K., Li, L., & Boussiotis, V. A. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00172 · Cited by 81
RNAi targeting EZH2 inhibits tumor growth and liver metastasis of pancreatic cancer in vivo
Chen, Y., Xie, D., Li, W. Y., Cheung, C. M., Yao, H., Chan, C. Y., Chan, C., Xu, F.-P., Liu, Y. H., Sung, J. J. �., et al. (2010) · Cancer Letters · doi:10.1016/j.canlet.2010.05.003 · Cited by 66
C/EBPϵ interacts with retinoblastoma and E2F1 during granulopoiesis
Gery, S., Gombart, A. F., Fung, Y. K., & Koeffler, H. P. (2003) · Blood · doi:10.1182/blood-2003-01-0159 · Cited by 63
Chen, G., Subedi, K., Chakraborty, S., Sharov, A. A., Lü, J., Kim, J., Mi, X., Wersto, R. P., Sung, M., & Weng, N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00549 · Cited by 56
Xia, S., Li, X., Cheng, L., Han, M., Zhang, M., Liu, X., Xu, H., Zhang, M., Shao, Q., & Qi, L. (2014) · Cancer Immunology Immunotherapy · doi:10.1007/s00262-014-1546-7 · Cited by 20
Will we be able to afford a cure in multiple myeloma?
Chakraborty, R., & Gertz, M. A. (2017) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2017.1339883 · Cited by 18
Kim, K., Hwang, S. M., Kim, S. M., Park, S. W., Jung, Y., & Chung, I. Y. (2017) · Immune Network · doi:10.4110/in.2017.17.6.410 · Cited by 14
LPS independent activation of the pro-inflammatory receptor Trem1 by C/EBPε in granulocytes
Suh, H. C., Benoukraf, T., Shyamsunder, P., Tong, Y., Cao, Q., SAID, J. W., Lee, S., Lim, R., Yang, H. H., Salotti, J., et al. (2017) · Scientific Reports · doi:10.1038/srep46440 · Cited by 9
Cited by
Sorted by citations
Inflammation and tumor progression: signaling pathways and targeted intervention
Zhao, H., Wu, L., Yan, G., Chen, Y., Zhou, M., Wu, Y., & Li, Y. (2021) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-021-00658-5 · Cited by 3,058
EZH2: a novel target for cancer treatment
Duan, R., Du, W., & Guo, W. (2020) · Journal of Hematology & Oncology · doi:10.1186/s13045-020-00937-8 · Cited by 980
Turning Cold into Hot: Firing up the Tumor Microenvironment
Duan, Q., Zhang, H., Zheng, J., & Zhang, L. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.02.022 · Cited by 934
Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise
Morel, D., Jeffery, D., Aspeslagh, S., Almouzni, G., & Postel-Vinay, S. C. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0267-4 · Cited by 473
Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets
Yang, J., Xu, J., Wang, W. T., Zhang, B., Yu, X., & Shi, S. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01480-x · Cited by 412
“GSK126 was also found to be associated with increased nfiltration MDSCs and fewer CD4 and IFNγCD8 T cells.(396) Muscle-invasive bladder cancer cells with KMD6A and SWI/SNF mutations were more sensitive to an EZH2 inhibitor (EPZ011989), which is mediated by enhanced NK cell-related signaling, resulting in tumor cell di…”
Background
Metadata
- Authors
- Huang, S., Wang, Z., Zhou, J., Huang, J., Zhou, L., Luo, J., Wan, Y. Y., Long, H., & Zhu, B.
- Affiliations
- Army Medical University (CN)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Long, Haixia
- Zhu, Bo
- Venue
- Cancer Research
- Published
- 2019-04-15
- Volume
- 79
- Issue
- 8
- Pages
- 2009-2020
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2911341716
- Cited by
- 185
- References
- 43
- Citations by year
- 2026: 10 · 2025: 28 · 2024: 28 · 2023: 30 · 2022: 29 · 2021: 29 · 2020: 21 · 2019: 9
- FWCI
- 8.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Nature Science Foundation of China (81472648, 81802865, and 81620108023)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- EZH2, GSK126, EZH2 inhibitors, myeloid-derived suppressor cells, antitumor immunity, tumor immune microenvironment, CD4+ T cells, CD8+ T cells, interferon-gamma, Gr-1, hematopoietic progenitor cells, myeloid differentiation, epigenetic regulation, combination therapy
- MeSH terms
- Enhancer of Zeste Homolog 2 Protein, Myeloid-Derived Suppressor Cells, Animals, Colonic Neoplasms, Female, Humans, Indoles, Mice, Inbred C57BL, Mice, Nude, Pyridones, Tumor Cells, Cultured, Apoptosis, CD8-Positive T-Lymphocytes, Carcinoma, Lewis Lung, Receptors, Chemokine, Xenograft Model Antitumor Assays, Cell Proliferation, Mice, Antibodies, Neutralizing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
