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Tumor Biology

, Volume 36, Issue 5, pp 3727–3734 | Cite as

Comparison of circulating and intratumoral regulatory T cells in patients with renal cell carcinoma

  • Gati Asma
  • Gorrab Amal
  • Marrakchi Raja
  • Derouiche Amine
  • Chebil Mohammed
  • Ben Ammar Elgaaied Amel
Research Article

Abstract

The clear evidence that tumor-infiltrating lymphocytes (TIL) exists in the tumor microenvironment raises the question why renal cell carcinoma (RCC) progresses. Numerous studies support the implication of CD4+CD25high regulatory T (Treg) cells in RCC development. We aimed in this study to characterize the phenotype and function of circulating and intratumoral Treg cells of RCC patient in order to evaluate their implication in the inhibition of the local antitumor immune response. Our results demonstrate that the proportion of Treg in TIL was, in average, similar to that found in circulating CD4+ T cells of patients or healthy donors. However, intratumoral Treg exhibit a marked different phenotype when compared with the autologous circulating Treg. A higher CD25 mean level, HLA-DR, Fas, and GITR, and a lower CD45RA expression were observed in intratumoral Treg, suggesting therefore that these cells are effector in the tumor microenvironment. Additionally, intratumoral Treg showed a higher inhibitory function on autologous CD4+CD25 T cells when compared with circulating Treg that may be explained by an overexpression of FoxP3 transcription factor. These findings suggest that intratumoral Treg could be major actors in the impairment of local antitumor immune response for RCC patients.

Keywords

RCC Tumor infiltrate Regulatory T cells Immune response Tumor escape 

Notes

Acknowledgments

This work was financially supported by the “PHC Utique” program of the French Ministry of Foreign Affairs and Ministry of higher education and research and the Tunisian Ministry of higher education and scientific research in the CMCU project number 13G0819.

Conflicts of interest

None

References

  1. 1.
    Chow WH, Dong LM, Devesa SS. Epidemiology and risk factors for kidney cancer. Nat Rev Urol. 2010;7:245–57.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol. 2006;49:798–805.CrossRefPubMedGoogle Scholar
  3. 3.
    Logan JE, Rampersaud EN, Sonn GA, Chamie K, Belldegrun AS, Pantuck AJ, et al. Systemic therapy for metastatic renal cell carcinoma: a review and update. Rev Urol. 2012;14:65–78.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Escudier B. Emerging immunotherapies for renal cell carcinoma. Ann Oncol. 2012;23 Suppl 8:viii35–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Dannenmann SR, Hermanns T, Bransi A, Matter C, von Boehmer L, Stevanovic S, et al. Spontaneous peripheral T-cell responses toward the tumor-associated antigen cyclin d1 in patients with clear cell renal cell carcinoma. Cancer Immunol Res. 2013;1:288–95.CrossRefPubMedGoogle Scholar
  6. 6.
    Mulders P, Bleumer I, Oosterwijk E. Tumor antigens and markers in renal cell carcinoma. Urol Clin N Am. 2003;30:455–65.CrossRefGoogle Scholar
  7. 7.
    Jochems C, Schlom J. Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity. Exp Biol Med (Maywood). 2011;236:567–79.CrossRefGoogle Scholar
  8. 8.
    Gati A, Guerra N, Giron-Michel J, Azzarone B, Angevin E, Moretta A, et al. Tumor cells regulate the lytic activity of tumor-specific cytotoxic T lymphocytes by modulating the inhibitory natural killer receptor function. Cancer Res. 2001;61:3240–4.PubMedGoogle Scholar
  9. 9.
    Wang HY, Lee DA, Peng G, Guo Z, Li Y, Kiniwa Y, et al. Tumor-specific human CD4+ regulatory T cells and their ligands: implications for immunotherapy. Immunity. 2004;20:107–18.CrossRefPubMedGoogle Scholar
  10. 10.
    Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, et al. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006;24:5373–80.CrossRefPubMedGoogle Scholar
  11. 11.
    Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004;10:942–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Zou W. Regulatory T cells, tumour immunity and immunotherapy. Nat Rev Immunol. 2006;6:295–307.CrossRefPubMedGoogle Scholar
  13. 13.
    Griffiths RW, Elkord E, Gilham DE, Ramani V, Clarke N, Stern PL, et al. Frequency of regulatory T cells in renal cell carcinoma patients and investigation of correlation with survival. Cancer Immunol Immunother. 2007;56:1743–53.CrossRefPubMedGoogle Scholar
  14. 14.
    Liotta F, Gacci M, Frosali F, Querci V, Vittori G, Lapini A, et al. Frequency of regulatory T cells in peripheral blood and in tumour-infiltrating lymphocytes correlates with poor prognosis in renal cell carcinoma. BJU Int. 2011;107:1500–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Siddiqui SA, Frigola X, Bonne-Annee S, Mercader M, Kuntz SM, Krambeck AE, et al. Tumor-infiltrating FoxP3–CD4+CD25+ T cells predict poor survival in renal cell carcinoma. Clin Cancer Res. 2007;13:2075–81.CrossRefPubMedGoogle Scholar
  16. 16.
    Beyer M, Kochanek M, Darabi K, Popov A, Jensen M, Endl E, et al. Reduced frequencies and suppressive function of CD4+CD25hi regulatory t cells in patients with chronic lymphocytic leukemia after therapy with fludarabine. Blood. 2005;106:2018–25.CrossRefPubMedGoogle Scholar
  17. 17.
    Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.CrossRefPubMedGoogle Scholar
  18. 18.
    Minarik I, Lastovicka J, Budinsky V, Kayserova J, Spisek R, Jarolim L, et al. Regulatory T cells, dendritic cells and neutrophils in patients with renal cell carcinoma. Immunol Lett. 2013;152:144–50.CrossRefPubMedGoogle Scholar
  19. 19.
    Polimeno M, Napolitano M, Costantini S, Portella L, Esposito A, Capone F, et al. 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. 2013;112:686–96.CrossRefPubMedGoogle Scholar
  20. 20.
    Hase S, Weinitschke K, Fischer K, Fornara P, Hoda R, Unverzagt S, et al. Monitoring peri-operative immune suppression in renal cancer patients. Oncol Rep. 2011;25:1455–64.PubMedGoogle Scholar
  21. 21.
    Morikawa H, Sakaguchi S. Genetic and epigenetic basis of Treg cell development and function: from a FoxP3-centered view to an epigenome-defined view of natural Treg cells. Immunol Rev. 2014;259:192–205.CrossRefPubMedGoogle Scholar
  22. 22.
    Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, et al. Activation-induced FoxP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19:345–54.CrossRefPubMedGoogle Scholar
  23. 23.
    Tran DQ, Ramsey H, Shevach EM. Induction of FoxP3 expression in naive human CD4+FoxP3 T cells by t-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood. 2007;110:2983–90.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FoxP3 in human activated nonregulatory CD4+ T cells. Eur J Immunol. 2007;37:129–38.CrossRefPubMedGoogle Scholar
  25. 25.
    Heiber JF, Geiger TL. Context and location dependence of adaptive FoxP3(+) regulatory T cell formation during immunopathological conditions. Cell Immunol. 2012;279:60–5.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Malchow S, Leventhal DS, Nishi S, Fischer BI, Shen L, Paner GP, et al. Aire-dependent thymic development of tumor-associated regulatory T cells. Science. 2013;339:1219–24.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Wainwright DA, Sengupta S, Han Y, Lesniak MS. Thymus-derived rather than tumor-induced regulatory T cells predominate in brain tumors. Neuro Oncol. 2011;13:1308–23.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Kim CS, Kim Y, Kwon T, Yoon JH, Kim KH, You D, Hong JH, Ahn H, Jeong IG: Regulatory T cells and TGF-beta1 in clinically localized renal cell carcinoma: comparison with age-matched healthy controls. Urol Oncol 2014. doi: 10.1016/j.urolonc.2014.11.004.
  29. 29.
    Yang L. TGFbeta, a potent regulator of tumor microenvironment and host immune response, implication for therapy. Curr Mol Med. 2010;10:374–80.CrossRefPubMedGoogle Scholar
  30. 30.
    Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25 T cells through FoxP3 induction and down-regulation of smad7. J Immunol. 2004;172:5149–53.CrossRefPubMedGoogle Scholar
  31. 31.
    Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, et al. Conversion of peripheral CD4+CD25 naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor FoxP3. J Exp Med. 2003;198:1875–86.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Moo-Young TA, Larson JW, Belt BA, Tan MC, Hawkins WG, Eberlein TJ, et al. Tumor-derived tgf-beta mediates conversion of CD4+FoxP3+ regulatory T cells in a murine model of pancreas cancer. J Immunother. 2009;32:12–21.CrossRefPubMedGoogle Scholar
  33. 33.
    Zou W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat Rev Cancer. 2005;5:263–74.CrossRefPubMedGoogle Scholar
  34. 34.
    Huang B, Pan PY, Li Q, Sato AI, Levy DE, Bromberg J, et al. Gr-1+CD115+ immature myeloid suppressor cells mediate the development of tumor-induced T regulatory cells and T-cell energy in tumor-bearing host. Cancer Res. 2006;66:1123–31.CrossRefPubMedGoogle Scholar
  35. 35.
    Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med. 2005;202:919–29.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Gati Asma
    • 1
    • 3
  • Gorrab Amal
    • 1
  • Marrakchi Raja
    • 1
  • Derouiche Amine
    • 2
  • Chebil Mohammed
    • 2
  • Ben Ammar Elgaaied Amel
    • 1
  1. 1.Laboratoire de Génétique, d’Immunologie et de pathologies humainesFaculté des Sciences de TunisTunisTunisia
  2. 2.Service d’UrologieHôpital Charles NicolleTunisTunisia
  3. 3.Department de biologieFaculté des sciences de TunisTunisTunisia

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