High level of EZH2 expression is linked to high density of CD8-positive T-lymphocytes and an aggressive phenotype in renal cell carcinoma.


Journal

World journal of urology
ISSN: 1433-8726
Titre abrégé: World J Urol
Pays: Germany
ID NLM: 8307716

Informations de publication

Date de publication:
Feb 2021
Historique:
received: 06 11 2019
accepted: 03 04 2020
pubmed: 19 4 2020
medline: 23 7 2021
entrez: 19 4 2020
Statut: ppublish

Résumé

Enhancer of zeste homolog 2 (EZH2), the catalytic part of the Polycomb repressive complex 2 (PRC2), has a prognostic role in renal cell carcinoma (RCC) and was recently shown to modulate the immune response by reducing tumor cell immunogenicity. To investigate whether the prognostic role of EZH2 might be driven by a modified immune environment, more than 1800 RCCs were analyzed in a tissue microarray for EZH2 expression and CD8 positive lymphocytes were quantitated by automated digital imaging. EZH2 positivity was found in 75.2% of 1603 interpretable tumors. In clear cell RCC, high EZH2 expression was significantly linked to high ISUP, Furmann, and Thoenes grade (p < 0.0001 each), advanced stage (p < 0.0001), nodal (p = 0.0190) and distant metastasis (p < 0.0001) as well as shortened overall (p < 0.0027) and recurrence free survival (p < 0.0001). The density of CD8+ cells varied from 0 to 5048 cells/mm Our data support a striking prognostic role of both EZH2 expression and the density of CD8+ cells in RCC. The tight relationship of EZH2 expression and CD8+ cell counts in RCC is consistent with models suggesting that EZH2 overexpression can be caused by high lymphocyte content in certain tumor types. Such a mechanism could explain the unique finding of high lymphocyte counts driving poor prognosis in RCC patients.

Identifiants

pubmed: 32303902
doi: 10.1007/s00345-020-03200-4
pii: 10.1007/s00345-020-03200-4
pmc: PMC7910252
doi:

Substances chimiques

EZH2 protein, human EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

481-490

Références

Jonasch E, Gao J, Rathmell WK (2014) Renal cell carcinoma. BMJ 349:g4797
pubmed: 25385470 pmcid: 4707715
Motzer RJ, Tannir NM, McDermott DF, Aren Frontera O, Melichar B, Choueiri TK et al (2018) Nivolumab plus Ipilimumab versus Sunitinib in advanced renal-cell carcinoma. N Engl J Med 378:1277–1290
pubmed: 29562145 pmcid: 5972549
Choueiri TK, Halabi S, Sanford BL, Hahn O, Michaelson MD, Walsh MK et al (2017) Cabozantinib versus Sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the alliance A031203 CABOSUN trial. J Clin Oncol 35:591–597
pubmed: 28199818
Addeo A, Banna GL, Metro G, Di Maio M (2019) Chemotherapy in combination with immune checkpoint inhibitors for the first-line treatment of patients with advanced non-small cell lung cancer: a systematic review and literature-based meta-analysis. Front Oncol 9:264
pubmed: 31058078 pmcid: 6478036
Katz H, Biglow L, Alsharedi M (2019) Immune checkpoint inhibitors in locally advanced, unresectable, and metastatic upper gastrointestinal malignancies. J Gastrointest Cancer. https://doi.org/10.1007/s12029-019-00243-8
doi: 10.1007/s12029-019-00243-8
Khair DO, Bax HJ, Mele S, Crescioli S, Pellizzari G, Khiabany A et al (2019) Combining immune checkpoint inhibitors: established and emerging targets and strategies to improve outcomes in melanoma. Front Immunol 10:453
pubmed: 6435047 pmcid: 6435047
Ljungberg B, Albiges L, Abu-Ghanem Y, Bensalah K, Dabestani S, Fernandez-Pello S et al (2019) European association of urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol 75:799–810
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D et al (2019) Pembrolizumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1116–1127
pubmed: 30779529
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT et al (2019) Avelumab plus Axitinib versus Sunitinib for advanced renal-cell carcinoma. N Engl J Med 380:1103–1115
pubmed: 30779531 pmcid: 6716603
Sauvageau M, Sauvageau G (2010) Polycomb group proteins: multi-faceted regulators of somatic stem cells and cancer. Cell Stem Cell 7:299–313
pubmed: 20804967 pmcid: 4959883
Cao Q, Yu J, Dhanasekaran SM, Kim JH, Mani RS, Tomlins SA et al (2008) Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27:7274–7284
pubmed: 18806826 pmcid: 2690514
Kotake Y, Cao R, Viatour P, Sage J, Zhang Y, Xiong Y (2007) pRB family proteins are required for H3K27 trimethylation and polycomb repression complexes binding to and silencing p16INK4alpha tumor suppressor gene. Genes Dev 21:49–54
pubmed: 17210787 pmcid: 1759899
Kim E, Kim M, Woo DH, Shin Y, Shin J, Chang N et al (2013) Phosphorylation of EZH2 activates STAT3 signaling via STAT3 methylation and promotes tumorigenicity of glioblastoma stem-like cells. Cancer Cell 23:839–852
pubmed: 23684459 pmcid: 4109796
Liu L, Xu Z, Zhong L, Wang H, Jiang S, Long Q et al (2013) Prognostic value of EZH2 expression and activity in renal cell carcinoma: a prospective study. PLoS ONE 8:e81484
pubmed: 24312307 pmcid: 3842247
Sun C, Zhao C, Li S, Wang J, Zhou Q, Sun J et al (2018) EZH2 expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis. J Cancer 9:3787–3796
pubmed: 30405850 pmcid: 6215999
Wagener N, Macher-Goeppinger S, Pritsch M, Husing J, Hoppe-Seyler K, Schirmacher P et al (2010) Enhancer of zeste homolog 2 (EZH2) expression is an independent prognostic factor in renal cell carcinoma. BMC Cancer 10:524
pubmed: 20920340 pmcid: 2958940
Wang Y, Chen Y, Geng H, Qi C, Liu Y, Yue D (2015) Overexpression of YB1 and EZH2 are associated with cancer metastasis and poor prognosis in renal cell carcinomas. Tumour Biol 36:7159–7166
pubmed: 25877750
Xu B, Abourbih S, Sircar K, Kassouf W, Mansure JJ, Aprikian A et al (2013) Enhancer of zeste homolog 2 expression is associated with metastasis and adverse clinical outcome in clear cell renal cell carcinoma: a comparative study and review of the literature. Arch Pathol Lab Med 137:1326–1336
pubmed: 24079759
Xu ZQ, Zhang L, Gao BS, Wan YG, Zhang XH, Chen B et al (2015) EZH2 promotes tumor progression by increasing VEGF expression in clear cell renal cell carcinoma. Clin Transl Oncol 17:41–49
pubmed: 24986100
Ho TH, Kapur P, Eckel-Passow JE, Christie A, Joseph RW, Serie DJ et al (2017) Multicenter validation of enhancer of zeste homolog 2 expression as an independent prognostic marker in localized clear cell renal cell carcinoma. J Clin Oncol 35:3706–3713
pubmed: 28976794 pmcid: 5678341
Lee HW, Choe M (2012) Expression of EZH2 in renal cell carcinoma as a novel prognostic marker. Pathol Int 62:735–741
pubmed: 23121604
Sakurai T, Bilim VN, Ugolkov AV, Yuuki K, Tsukigi M, Motoyama T et al (2012) The enhancer of zeste homolog 2 (EZH2), a potential therapeutic target, is regulated by miR-101 in renal cancer cells. Biochem Biophys Res Commun 422:607–614
pubmed: 22609199
Zingg D, Arenas-Ramirez N, Sahin D, Rosalia RA, Antunes AT, Haeusel J et al (2017) The histone methyltransferase Ezh2 controls mechanisms of adaptive resistance to tumor immunotherapy. Cell Rep 20:854–867
pubmed: 28746871
Eichelberg C, Minner S, Isbarn H, Burandt E, Terracciano L, Moch H et al (2013) Prognostic value of alpha-methyl CoA racemase (AMACR) expression in renal cell carcinoma. World J Urol 31:847–853
pubmed: 22009118
Kononen J, Bubendorf L, Kallioniemi A, Barlund M, Schraml P, Leighton S et al (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4:844–847
pubmed: 9662379
Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C et al (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960–1964
pubmed: 17008531
Hinz S, Weikert S, Magheli A, Hoffmann M, Engers R, Miller K et al (2009) Expression profile of the polycomb group protein enhancer of zeste homologue 2 and its prognostic relevance in renal cell carcinoma. J Urol 182:2920–2925
pubmed: 19846140
Liu L, Xu Z, Zhong L, Wang H, Jiang S, Long Q et al (2016) Enhancer of zeste homolog 2 (EZH2) promotes tumour cell migration and invasion via epigenetic repression of E-cadherin in renal cell carcinoma. BJU Int 117:351–362
pubmed: 24612432
Hirata H, Hinoda Y, Shahryari V, Deng G, Nakajima K, Tabatabai ZL et al (2015) Long noncoding RNA MALAT1 promotes aggressive renal cell carcinoma through Ezh2 and interacts with miR-205. Cancer Res 75:1322–1331
pubmed: 25600645 pmcid: 5884967
Nocito A, Bubendorf L, Tinner EM, Suess K, Wagner U, Forster T et al (2001) Microarrays of bladder cancer tissue are highly representative of proliferation index and histological grade. J Pathol 194:349–357
pubmed: 11439368
Schroeder C, Navid-Hill E, Meiners J, Hube-Magg C, Kluth M, Makrypidi-Fraune G et al (2019) Nuclear ELAC2 overexpression is associated with increased hazard for relapse after radical prostatectomy. Oncotarget 10:4973–4986
pubmed: 31452838 pmcid: 6697635
Kluth M, Runte F, Barow P, Omari J, Abdelaziz ZM, Paustian L et al (2015) Concurrent deletion of 16q23 and PTEN is an independent prognostic feature in prostate cancer. Int J Cancer 137:2354–2363
pubmed: 26009879
Burdelski C, Matuszewska A, Kluth M, Koop C, Grupp K, Steurer S et al (2014) Qualitative and quantitative requirements for assessing prognostic markers in prostate cancer. Microarrays (Basel) 3:137–158
Fujikawa D, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K et al (2016) Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood 127:1790–1802
pubmed: 26773042
Rajabi H, Hiraki M, Tagde A, Alam M, Bouillez A, Christensen CL et al (2017) MUC1-C activates EZH2 expression and function in human cancer cells. Sci Rep 7:7481
pubmed: 28785086 pmcid: 5547076
Riquelme E, Behrens C, Lin HY, Simon G, Papadimitrakopoulou V, Izzo J et al (2016) Modulation of EZH2 expression by MEK-ERK or PI3K-AKT signaling in lung cancer is dictated by different KRAS oncogene mutations. Cancer Res 76:675–685
pubmed: 26676756
Komohara Y, Harada M, Arima Y, Suekane S, Noguchi M, Yamada A et al (2007) Identification of target antigens in specific immunotherapy for renal cell carcinoma. J Urol 177:1157–1162
pubmed: 17296437
Komohara Y, Harada M, Arima Y, Suekane S, Noguchi M, Yamada A et al (2006) Anti-cancer vaccine candidates in specific immunotherapy for bladder carcinoma. Int J Oncol 29:1555–1560
pubmed: 17088996
Minami T, Minami T, Shimizu N, Yamamoto Y, De Velasco MA, Nozawa M et al (2015) New polycomb group protein enhancer of zeste homolog (EZH) 2-derived peptide with the potential to induce cancer-reactive cytotoxic T lymphocytes in prostate cancer patients with HLA-A3 supertype alleles. Int Immunopharmacol 26:133–138
pubmed: 25819666
Nakano O, Sato M, Naito Y, Suzuki K, Orikasa S, Aizawa M et al (2001) Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res 61:5132–5136
pubmed: 11431351
Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S et al (2007) CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci USA 104:3967–3972
pubmed: 17360461
Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH et al (2011) Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol 29:1949–1955
pubmed: 21483002
Fukunaga A, Miyamoto M, Cho Y, Murakami S, Kawarada Y, Oshikiri T et al (2004) CD8+ tumor-infiltrating lymphocytes together with CD4+ tumor-infiltrating lymphocytes and dendritic cells improve the prognosis of patients with pancreatic adenocarcinoma. Pancreas 28:e26–e31
pubmed: 14707745
Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H et al (1998) CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res 58:3491–3494
pubmed: 9721846
Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH (2010) Immune infiltration in human tumors: a prognostic factor that should not be ignored. Oncogene 29:1093–1102
pubmed: 19946335
Bindea G, Mlecnik B, Fridman WH, Galon J (2011) The prognostic impact of anti-cancer immune response: a novel classification of cancer patients. Semin Immunopathol 33:335–340
pubmed: 21461991 pmcid: 3139059
Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C et al (2018) International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391:2128–2139
pubmed: 29754777
George DJ, Martini JF, Staehler M, Motzer RJ, Magheli A, Escudier B et al (2018) Immune biomarkers predictive for disease-free survival with adjuvant Sunitinib in high-risk locoregional renal cell carcinoma: from randomized phase III S-TRAC study. Clin Cancer Res 24:1554–1561
pubmed: 29374054
Yao J, Xi W, Zhu Y, Wang H, Hu X, Guo J (2018) Checkpoint molecule PD-1-assisted CD8(+) T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. Cancer Manag Res 10:3419–3431
pubmed: 30237743 pmcid: 6138960
Fridman WH, Zitvogel L, Sautes-Fridman C, Kroemer G (2017) The immune contexture in cancer prognosis and treatment. Nat Rev Clin Oncol 14:717–734
pubmed: 28741618

Auteurs

Till Eichenauer (T)

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Luca Simmendinger (L)

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Christoph Fraune (C)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Tim Mandelkow (T)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Niclas C Blessin (NC)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Martina Kluth (M)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Claudia Hube-Magg (C)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Katharina Möller (K)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Till Clauditz (T)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Sören Weidemann (S)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Roland Dahlem (R)

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Margit Fisch (M)

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Silke Riechardt (S)

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Ronald Simon (R)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany. r.simon@uke.de.

Guido Sauter (G)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Franziska Büscheck (F)

Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, 20246, Hamburg, Germany.

Michael Rink (M)

Department of Urology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female
Humans United States Aged Cross-Sectional Studies Medicare Part C
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH