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01-02-2016 | Original Article

Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients

Authors: Anastasia Dielmann, Anne Letsch, Anika Nonnenmacher, Kurt Miller, Ulrich Keilholz, Antonia Busse

Published in: Cancer Immunology, Immunotherapy | Issue 2/2016

Abstract

T-box transcription factors, T-box expressed in T cells (T-bet) encoded by Tbx21 and Eomesodermin (Eomes), drive the differentiation of effector/memory T cell lineages and NK cells. The aim of the study was to determine the prognostic influence of the expression of these transcription factors in peripheral blood (pB) in a cohort of 41 metastatic (m) RCC patients before receiving sorafenib treatment and to analyze their association with the immunophenotype in pB. In contrast to Tbx21, in the multivariate analysis including clinical features, Eomes mRNA expression was identified as an independent good prognostic factor for progression-free survival (PFS, p = 0.042) and overall survival (OS, p = 0.001) in addition to a favorable ECOG performance status (p = 0.01 and p = 0.008, respectively). Eomes expression correlated positively not only with expression of Tbx21 and TGFβ1 mRNA, but also with mRNA expression of the activation marker ICOS, and with in vivo activated HLA-DR⁺ T cells. Eomes expression was negatively associated with TNFα-producing T cells. On protein level, Eomes was mainly expressed by CD56⁺CD3⁻ NK cells in pB. In conclusion, we identified a higher Eomes mRNA expression as an independent good prognostic factor for OS and PFS in mRCC patients treated with sorafenib.

Busse A, Keilholz U (2010) Immune self-tuning in renal cell carcinoma. Eur Oncol 6(1):70–75

Knox JJ, Cosma GL, Betts MR, McLane LM (2014) Characterization of T-bet and eomes in peripheral human immune cells. Front Immunol 5:217. doi:10.3389/fimmu.2014.00217 PubMedCentralCrossRefPubMed

Intlekofer AM, Takemoto N, Wherry EJ, Longworth SA, Northrup JT, Palanivel VR, Mullen AC, Gasink CR, Kaech SM, Miller JD, Gapin L, Ryan K, Russ AP, Lindsten T, Orange JS, Goldrath AW, Ahmed R, Reiner SL (2005) Effector and memory CD8⁺ T cell fate coupled by T-bet and eomesodermin. Nat Immunol 6(12):1236–1244. doi:10.1038/ni1268 CrossRefPubMed

Rao RR, Li Q, Odunsi K, Shrikant PA (2010) The mTOR kinase determines effector versus memory CD8⁺ T cell fate by regulating the expression of transcription factors T-bet and Eomesodermin. Immunity 32(1):67–78. doi:10.1016/j.immuni.2009.10.010 CrossRefPubMed

Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, Lindsten T, Reiner SL (2012) The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36(1):55–67. doi:10.1016/j.immuni.2011.11.016 PubMedCentralCrossRefPubMed

Townsend MJ, Weinmann AS, Matsuda JL, Salomon R, Farnham PJ, Biron CA, Gapin L, Glimcher LH (2004) T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. Immunity 20(4):477–494CrossRefPubMed

Beuselinck B, Vano YA, Oudard S, Wolter P, De Smet R, Depoorter L, Teghom C, Karadimou A, Zucman-Rossi J, Debruyne PR, Van Poppel H, Joniau S, Lerut E, Strijbos M, Dumez H, Paridaens R, Van Calster B, Schoffski P (2014) Prognostic impact of baseline serum C-reactive protein in patients with metastatic renal cell carcinoma (RCC) treated with sunitinib. BJU Int 114(1):81–89. doi:10.1111/bju.12494 CrossRefPubMed

Zhu Y, Ju S, Chen E, Dai S, Li C, Morel P, Liu L, Zhang X, Lu B (2010) T-bet and eomesodermin are required for T cell-mediated antitumor immune responses. J Immunol 185(6):3174–3183. doi:10.4049/jimmunol.1000749 CrossRefPubMed

Pearce EL, Mullen AC, Martins GA, Krawczyk CM, Hutchins AS, Zediak VP, Banica M, DiCioccio CB, Gross DA, Mao CA, Shen H, Cereb N, Yang SY, Lindsten T, Rossant J, Hunter CA, Reiner SL (2003) Control of effector CD8⁺ T cell function by the transcription factor Eomesodermin. Science 302(5647):1041–1043. doi:10.1126/science.1090148 CrossRefPubMed

10.

Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK (2009) Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 27(34):5794–5799. doi:10.1200/JCO.2008.21.4809 CrossRefPubMed

11.

Yasuda Y, Saito K, Yuasa T, Kitsukawa S, Urakami S, Yamamoto S, Yonese J, Takahashi S, Fukui I (2013) Prognostic impact of pretreatment C-reactive protein for patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors. Int J Clin Oncol 18(5):884–889. doi:10.1007/s10147-012-0454-0 CrossRefPubMed

12.

Polimeno M, Napolitano M, Costantini S, Portella L, Esposito A, Capone F, Guerriero E, Trotta A, Zanotta S, Pucci L, Longo N, Perdona S, Pignata S, Castello G, Scala S (2013) Regulatory T cells, interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), CXCL10, CXCL11, epidermal growth factor (EGF) and hepatocyte growth factor (HGF) as surrogate markers of host immunity in patients with renal cell carcinoma. BJU Int 112(5):686–696. doi:10.1111/bju.12068 CrossRefPubMed

13.

Funakoshi T, Lee CH, Hsieh JJ (2014) A systematic review of predictive and prognostic biomarkers for VEGF-targeted therapy in renal cell carcinoma. Cancer Treat Rev 40(4):533–547. doi:10.1016/j.ctrv.2013.11.008 CrossRefPubMed

14.

Tran HT, Liu Y, Zurita AJ, Lin Y, Baker-Neblett KL, Martin AM, Figlin RA, Hutson TE, Sternberg CN, Amado RG, Pandite LN, Heymach JV (2012) Prognostic or predictive plasma cytokines and angiogenic factors for patients treated with pazopanib for metastatic renal-cell cancer: a retrospective analysis of phase 2 and phase 3 trials. Lancet Oncol 13(8):827–837. doi:10.1016/S1470-2045(12)70241-3 CrossRefPubMed

15.

Busse A, Asemissen A, Nonnenmacher A, Ochsenreither S, Fusi A, Braun F, Stather D, Schmittel A, Miller K, Thiel E, Keilholz U (2011) Systemic immune tuning in renal cell carcinoma: favorable prognostic impact of TGF-beta1 mRNA expression in peripheral blood mononuclear cells. J Immunother 34(1):113–119. doi:10.1097/CJI.0b013e3181fb6580 CrossRefPubMed

16.

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, Tosolini M, Camus M, Berger A, Wind P, Zinzindohoue F, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Pages F (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313(5795):1960–1964. doi:10.1126/science.1129139 CrossRefPubMed

17.

Pages F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, Mlecnik B, Kirilovsky A, Nilsson M, Damotte D, Meatchi T, Bruneval P, Cugnenc PH, Trajanoski Z, Fridman WH, Galon J (2005) Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med 353(25):2654–2666. doi:10.1056/NEJMoa051424 CrossRefPubMed

18.

Atreya I, Schimanski CC, Becker C, Wirtz S, Dornhoff H, Schnurer E, Berger MR, Galle PR, Herr W, Neurath MF (2007) The T-box transcription factor eomesodermin controls CD8 T cell activity and lymph node metastasis in human colorectal cancer. Gut 56(11):1572–1578. doi:10.1136/gut.2006.117812 PubMedCentralCrossRefPubMed

19.

Chen LJ, Zheng X, Shen YP, Zhu YB, Li Q, Chen J, Xia R, Zhou SM, Wu CP, Zhang XG, Lu BF, Jiang JT (2013) Higher numbers of T-bet(+) intratumoral lymphoid cells correlate with better survival in gastric cancer. Cancer Immunol Immunother 62(3):553–561. doi:10.1007/s00262-012-1358-6 CrossRefPubMed

20.

Therasse P (2002) Measuring the clinical response. What does it mean? Eur J Cancer 38(14):1817–1823CrossRefPubMed

21.

Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP (1982) Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5(6):649–655CrossRefPubMed

22.

Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M (2004) Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol 22(3):454–463CrossRefPubMed

23.

Busse A, Asemissen AM, Nonnenmacher A, Braun F, Ochsenreither S, Stather D, Fusi A, Schmittel A, Miller K, Thiel E, Keilholz U (2011) Immunomodulatory effects of sorafenib on peripheral immune effector cells in metastatic renal cell carcinoma. Eur J Cancer 47(5):690–696. doi:10.1016/j.ejca.2010.11.021 CrossRefPubMed

24.

Roosen JU, Engel U, Jensen RH, Kvist E, Schou G (1994) Renal cell carcinoma: prognostic factors. Br J Urol 74(2):160–164CrossRefPubMed

25.

Finley DS, Pantuck AJ, Belldegrun AS (2011) Tumor biology and prognostic factors in renal cell carcinoma. Oncologist 16(Suppl 2):4–13. doi:10.1634/theoncologist.2011-S2-04 PubMedCentralCrossRefPubMed

26.

Brannon AR, Haake SM, Hacker KE, Pruthi RS, Wallen EM, Nielsen ME, Rathmell WK (2012) Meta-analysis of clear cell renal cell carcinoma gene expression defines a variant subgroup and identifies gender influences on tumor biology. Eur Urol 61(2):258–268. doi:10.1016/j.eururo.2011.10.007 PubMedCentralCrossRefPubMed

27.

Maroto P, Rini B (2014) Molecular biomarkers in advanced renal cell carcinoma. Clin Cancer Res 20(8):2060–2071. doi:10.1158/1078-0432.CCR-13-1351 CrossRefPubMed

28.

Poli A, Michel T, Theresine M, Andres E, Hentges F, Zimmer J (2009) CD56bright natural killer (NK) cells: an important NK cell subset. Immunology 126(4):458–465. doi:10.1111/j.1365-2567.2008.03027.x PubMedCentralCrossRefPubMed

29.

Cheng M, Chen Y, Xiao W, Sun R, Tian Z (2013) NK cell-based immunotherapy for malignant diseases. Cell Mol Immunol 10(3):230–252. doi:10.1038/cmi.2013.10 PubMedCentralCrossRefPubMed

30.

Schleypen JS, Baur N, Kammerer R, Nelson PJ, Rohrmann K, Grone EF, Hohenfellner M, Haferkamp A, Pohla H, Schendel DJ, Falk CS, Noessner E (2006) Cytotoxic markers and frequency predict functional capacity of natural killer cells infiltrating renal cell carcinoma. Clin Cancer Res 12(3 Pt 1):718–725. doi:10.1158/1078-0432.CCR-05-0857 CrossRefPubMed

31.

Takai S, Schlom J, Tucker J, Tsang KY, Greiner JW (2013) Inhibition of TGF-beta1 signaling promotes central memory T cell differentiation. J Immunol 191(5):2299–2307. doi:10.4049/jimmunol.1300472 PubMedCentralCrossRefPubMed

32.

Mantovani A, Garlanda C, Allavena P (2010) Molecular pathways and targets in cancer-related inflammation. Ann Med 42(3):161–170. doi:10.3109/07853890903405753 CrossRefPubMed

33.

Tofukuji S, Kuwahara M, Suzuki J, Ohara O, Nakayama T, Yamashita M (2012) Identification of a new pathway for Th1 cell development induced by cooperative stimulation with IL-4 and TGF-beta. J Immunol 188(10):4846–4857. doi:10.4049/jimmunol.1103799 CrossRefPubMed

34.

Lingnau K, Hoehn P, Kerdine S, Koelsch S, Neudoerfl C, Palm N, Ruede E, Schmitt E (1998) IL-4 in combination with TGF-beta favors an alternative pathway of Th1 development independent of IL-12. J Immunol 161(9):4709–4718PubMed

35.

Eshima K, Chiba S, Suzuki H, Kokubo K, Kobayashi H, Iizuka M, Iwabuchi K, Shinohara N (2012) Ectopic expression of a T-box transcription factor, eomesodermin, renders CD4(+) Th cells cytotoxic by activating both perforin- and FasL-pathways. Immunol Lett 144(1–2):7–15. doi:10.1016/j.imlet.2012.02.013 CrossRefPubMed

36.

Hu Q, Gou Y, Sun C, Ding W, Xu K, Gu B, Xia G, Ding Q (2014) The prognostic value of C-reactive protein in renal cell carcinoma: a systematic review and meta-analysis. Urologic oncology 32(1):50e1–50e8. doi:10.1016/j.urolonc.2013.07.016 CrossRef

37.

Negrier S, Perol D, Menetrier-Caux C, Escudier B, Pallardy M, Ravaud A, Douillard JY, Chevreau C, Lasset C, Blay JY, Groupe Francais dI (2004) Interleukin-6, interleukin-10, and vascular endothelial growth factor in metastatic renal cell carcinoma: prognostic value of interleukin-6–from the Groupe Francais d’Immunotherapie. J Clin Oncol 22(12):2371–2378. doi:10.1200/JCO.2004.06.121 CrossRef

38.

Perez-Gracia JL, Prior C, Guillen-Grima F, Segura V, Gonzalez A, Panizo A, Melero I, Grande-Pulido E, Gurpide A, Gil-Bazo I, Calvo A (2009) Identification of TNF-alpha and MMP-9 as potential baseline predictive serum markers of sunitinib activity in patients with renal cell carcinoma using a human cytokine array. Br J Cancer 101(11):1876–1883. doi:10.1038/sj.bjc.6605409 PubMedCentralCrossRefPubMed

39.

Vermaat JS, van der Tweel I, Mehra N, Sleijfer S, Haanen JB, Roodhart JM, Engwegen JY, Korse CM, Langenberg MH, Kruit W, Groenewegen G, Giles RH, Schellens JH, Beijnen JH, Voest EE (2010) Two-protein signature of novel serological markers apolipoprotein-A2 and serum amyloid alpha predicts prognosis in patients with metastatic renal cell cancer and improves the currently used prognostic survival models. Ann Oncol 21(7):1472–1481. doi:10.1093/annonc/mdp559 CrossRefPubMed

40.

Sengupta S, Lohse CM, Cheville JC, Leibovich BC, Thompson RH, Webster WS, Frank I, Zincke H, Blute ML, Kwon ED (2006) The preoperative erythrocyte sedimentation rate is an independent prognostic factor in renal cell carcinoma. Cancer 106(2):304–312. doi:10.1002/cncr.21617 CrossRefPubMed

41.

Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH (2000) A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100(6):655–669CrossRefPubMed

42.

Ylikoski E, Lund R, Kylaniemi M, Filen S, Kilpelainen M, Savolainen J, Lahesmaa R (2005) IL-12 up-regulates T-bet independently of IFN-gamma in human CD4⁺ T cells. Eur J Immunol 35(11):3297–3306. doi:10.1002/eji.200526101 CrossRefPubMed

43.

Lin JT, Martin SL, Xia L, Gorham JD (2005) TGF-beta 1 uses distinct mechanisms to inhibit IFN-gamma expression in CD4⁺ T cells at priming and at recall: differential involvement of Stat4 and T-bet. J Immunol 174(10):5950–5958CrossRefPubMed

44.

Garcia-Roig M, Ortiz N, Lokeshwar V (2014) Molecular marker for predicting treatment response in advanced renal cell carcinoma: does the promise fulfill clinical need? Curr Urol Rep 15(1):375. doi:10.1007/s11934-013-0375-0 PubMedCentralCrossRefPubMed

45.

Porta C, Paglino C, De Amici M, Quaglini S, Sacchi L, Imarisio I, Canipari C (2010) Predictive value of baseline serum vascular endothelial growth factor and neutrophil gelatinase-associated lipocalin in advanced kidney cancer patients receiving sunitinib. Kidney Int 77(9):809–815. doi:10.1038/ki.2009.552 CrossRefPubMed

46.

Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, Negrier S, Chevreau C, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Anderson S, Hofilena G, Shan M, Pena C, Lathia C, Bukowski RM (2009) Sorafenib for treatment of renal cell carcinoma: Final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol 27(20):3312–3318CrossRefPubMed

47.

Harmon CS, DePrimo SE, Figlin RA, Hudes GR, Hutson TE, Michaelson MD, Negrier S, Kim ST, Huang X, Williams JA, Eisen T, Motzer RJ (2014) Circulating proteins as potential biomarkers of sunitinib and interferon-alpha efficacy in treatment-naive patients with metastatic renal cell carcinoma. Cancer Chemother Pharmacol 73(1):151–161. doi:10.1007/s00280-013-2333-4 PubMedCentralCrossRefPubMed

48.

Pena C, Lathia C, Shan M, Escudier B, Bukowski RM (2010) Biomarkers predicting outcome in patients with advanced renal cell carcinoma: Results from sorafenib phase III Treatment Approaches in Renal Cancer Global Evaluation Trial. Clin Cancer Res 16(19):4853–4863. doi:10.1158/1078-0432.CCR-09-3343 CrossRefPubMed

49.

Zurita AJ, Jonasch E, Wang X, Khajavi M, Yan S, Du DZ, Xu L, Herynk MH, McKee KS, Tran HT, Logothetis CJ, Tannir NM, Heymach JV (2012) A cytokine and angiogenic factor (CAF) analysis in plasma for selection of sorafenib therapy in patients with metastatic renal cell carcinoma. Ann Oncol 23(1):46–52. doi:10.1093/annonc/mdr047 PubMedCentralCrossRefPubMed

50.

Hertoghs KM, Moerland PD, van Stijn A, Remmerswaal EB, Yong SL, van de Berg PJ, van Ham SM, Baas F, ten Berge IJ, van Lier RA (2010) Molecular profiling of cytomegalovirus-induced human CD8⁺ T cell differentiation. J Clin Investig 120(11):4077–4090. doi:10.1172/JCI42758 PubMedCentralCrossRefPubMed

Title: Favorable prognostic influence of T-box transcription factor Eomesodermin in metastatic renal cell cancer patients
Authors: Anastasia Dielmann
Anne Letsch
Anika Nonnenmacher
Kurt Miller
Ulrich Keilholz
Antonia Busse
Publication date: 01-02-2016
Publisher: Springer Berlin Heidelberg
Published in: Cancer Immunology, Immunotherapy / Issue 2/2016
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI: https://doi.org/10.1007/s00262-015-1786-1

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