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Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival

Abstract

Regulatory T (Treg) cells mediate homeostatic peripheral tolerance by suppressing autoreactive T cells. Failure of host antitumor immunity may be caused by exaggerated suppression of tumor-associated antigen–reactive lymphocytes mediated by Treg cells; however, definitive evidence that Treg cells have an immunopathological role in human cancer is lacking. Here we show, in detailed studies of CD4+CD25+FOXP3+ Treg cells in 104 individuals affected with ovarian carcinoma, that human tumor Treg cells suppress tumor-specific T cell immunity and contribute to growth of human tumors in vivo. We also show that tumor Treg cells are associated with a high death hazard and reduced survival. Human Treg cells preferentially move to and accumulate in tumors and ascites, but rarely enter draining lymph nodes in later cancer stages. Tumor cells and microenvironmental macrophages produce the chemokine CCL22, which mediates trafficking of Treg cells to the tumor. This specific recruitment of Treg cells represents a mechanism by which tumors may foster immune privilege. Thus, blocking Treg cell migration or function may help to defeat human cancer.

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Figure 1: CD4+CD25+ T cells in distinct tumor microenvironments.
Figure 2: CD4+CD25+ T cells in lymph nodes.
Figure 3: Tumor Treg cells suppress T cell activation in vitro.
Figure 4: A CCL22-CCR4 signal mediates CD4+CD25+ Treg cells migration.
Figure 5: Tumor Treg cells inhibit TAA-specific T cell immunity.
Figure 6: Accumulation of tumor Treg cells predicts poor survival in individuals with ovarian carcinoma.

References

  1. Romero, P. et al. Ex vivo staining of metastatic lymph nodes by class I major histocompatibility complex tetramers reveals high numbers of antigen-experienced tumor-specific cytolytic T lymphocytes. J. Exp. Med. 188, 1641–1650 (1998).

    Article  CAS  Google Scholar 

  2. Lee, P.P. et al. Characterization of circulating T cells specific for tumor-associated antigens in melanoma patients. Nat. Med. 5, 677–685 (1999).

    Article  CAS  Google Scholar 

  3. Salio, M. et al. Mature dendritic cells prime functionally superior melan-A–specific CD8+ lymphocytes as compared with nonprofessional APC. J. Immunol. 167, 1188–1197 (2001).

    Article  CAS  Google Scholar 

  4. Dunbar, P.R. et al. A shift in the phenotype of melan-A-specific CTL identifies melanoma patients with an active tumor-specific immune response. J. Immunol. 165, 6644–6652 (2000).

    Article  CAS  Google Scholar 

  5. Curiel, T.J. et al. Blockade of B7-H1 improves myeloid dendritic cell–mediated antitumor immunity. Nat. Med. 9, 562–567 (2003).

    Article  CAS  Google Scholar 

  6. Yee, C., Riddell, S.R. & Greenberg, P.D. Prospects for adoptive T cell therapy. Curr. Opin. Immunol. 9, 702–708 (1997).

    Article  CAS  Google Scholar 

  7. Maio, M. & Parmiani, G. Melanoma immunotherapy: new dreams or solid hopes? Immunol. Today 17, 405–407 (1996).

    Article  CAS  Google Scholar 

  8. Maeurer, M.J., Storkus, W.J., Kirkwood, J.M. & Lotze, M.T. New treatment options for patients with melanoma: review of melanoma-derived T-cell epitope–based peptide vaccines. Melanoma Res. 6, 11–24 (1996).

    Article  CAS  Google Scholar 

  9. Pardoll, D. Does the immune system see tumors as foreign or self? Annu. Rev. Immunol. 21, 807–839 (2003).

    Article  CAS  Google Scholar 

  10. Pardoll, D. T cells and tumours. Nature 411, 1010–1012 (2001).

    Article  CAS  Google Scholar 

  11. Schreiber, H., Wu, T.H., Nachman, J. & Kast, W.M. Immunodominance and tumor escape. Semin. Cancer Biol. 12, 25–31 (2002).

    Article  CAS  Google Scholar 

  12. Munn, D.H. et al. Potential regulatory function of human dendritic cells expressing indoleamine 2,3-dioxygenase. Science 297, 1867–1870 (2002).

    Article  CAS  Google Scholar 

  13. Khong, H.T. & Restifo, N.P. Natural selection of tumor variants in the generation of 'tumor escape' phenotypes. Nat. Immunol. 3, 999–1005 (2002).

    Article  CAS  Google Scholar 

  14. Shevach, E.M. CD4+CD25+ suppressor T cells: more questions than answers. Nat. Rev. Immunol. 2, 389–400 (2002).

    Article  CAS  Google Scholar 

  15. Wood, K.J. & Sakaguchi, S. Regulatory lymphocytes: regulatory T cells in transplantation tolerance. Nat. Rev. Immunol. 3, 199–210 (2003).

    Article  CAS  Google Scholar 

  16. Von Herrath, M.G. & Harrison, L.C. Regulatory lymphocytes: antigen-induced regulatory T cells in autoimmunity. Nat. Rev. Immunol. 3, 223–232 (2003).

    Article  CAS  Google Scholar 

  17. Bach, J.F. Regulatory lymphocytes: regulatory T cells under scrutiny. Nat. Rev. Immunol. 3, 189–198 (2003).

    Article  Google Scholar 

  18. Read, S. & Powrie, F. CD4+ regulatory T cells. Curr. Opin. Immunol. 13, 644–649 (2001).

    Article  CAS  Google Scholar 

  19. Dieckmann, D., Plottner, H., Berchtold, S., Berger, T. & Schuler, G. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J. Exp. Med. 193, 1303–1310 (2001).

    Article  CAS  Google Scholar 

  20. Ng, W.F. et al. Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 98, 2736–2744 (2001).

    Article  CAS  Google Scholar 

  21. Levings, M.K., Sangregorio, R. & Roncarolo, M.G. Human CD25+CD4+ T regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J. Exp. Med. 193, 1295–1302 (2001).

    Article  CAS  Google Scholar 

  22. Woo, E.Y. et al. Regulatory CD4+CD25+ T cells in tumors from patients with early-stage non-small cell lung cancer and late-stage ovarian cancer. Cancer Res. 61, 4766–4772 (2001).

    CAS  PubMed  Google Scholar 

  23. Woo, E.Y. et al. Regulatory T cells from lung cancer patients directly inhibit autologous T cell proliferation. J. Immunol. 168, 4272–4276 (2002).

    Article  CAS  Google Scholar 

  24. Liyanage, U.K. et al. Prevalence of regulatory T cells is increased in peripheral blood and tumor microenvironment of patients with pancreas or breast adenocarcinoma. J. Immunol. 169, 2756–2761 (2002).

    Article  CAS  Google Scholar 

  25. Hori, S., Nomura, T. & Sakaguchi, S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299, 1057–1061 (2003).

    Article  CAS  Google Scholar 

  26. Fontenot, J.D., Gavin, M.A. & Rudensky, A.Y. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4, 330–336 (2003).

    Article  CAS  Google Scholar 

  27. Khattri, R., Cox, T., Yasayko, S.A. & Ramsdell, F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat. Immunol. 4, 337–342 (2003).

    Article  CAS  Google Scholar 

  28. Sakaguchi, S. et al. Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol. Rev. 182, 18–32 (2001).

    Article  CAS  Google Scholar 

  29. Baecher-Allan, C., Brown, J.A., Freeman, G.J. & Hafler, D.A. CD4+CD25hi regulatory cells in human peripheral blood. J. Immunol. 167, 1245–1253 (2001).

    Article  CAS  Google Scholar 

  30. Zou, W. et al. Stromal-derived factor-1 in human tumors recruits and alters the function of plasmacytoid precursor dendritic cells. Nat. Med. 7, 1339–1346 (2001).

    Article  CAS  Google Scholar 

  31. Knutson, K.L., Schiffman, K. & Disis, M.L. Immunization with a HER-2/neu helper peptide vaccine generates HER-2/neu CD8 T-cell immunity in cancer patients. J. Clin. Invest. 107, 477–484 (2001).

    Article  CAS  Google Scholar 

  32. Baecher-Allan, C., Viglietta, V. & Hafler, D.A. Inhibition of human CD4+CD25hi regulatory T cell function. J. Immunol. 169, 6210–6217 (2002).

    Article  CAS  Google Scholar 

  33. Markman, M. Optimizing primary chemotherapy in ovarian cancer. Hematol. Oncol. Clin. North Am. 17, 957–968, viii (2003).

    Article  Google Scholar 

  34. Shevach, E.M. Regulatory T cells in autoimmmunity. Annu. Rev. Immunol. 18, 423–449 (2000).

    Article  CAS  Google Scholar 

  35. Taylor, P.A., Noelle, R.J. & Blazar, B.R. CD4+CD25+ immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J. Exp. Med. 193, 1311–1318 (2001).

    Article  CAS  Google Scholar 

  36. Taylor, P.A., Lees, C.J. & Blazar, B.R. The infusion of ex vivo activated and expanded CD4+CD25+ immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99, 3493–3499 (2002).

    Article  CAS  Google Scholar 

  37. Shimizu, J., Yamazaki, S. & Sakaguchi, S. Induction of tumor immunity by removing CD25+CD4+ T cells: a common basis between tumor immunity and autoimmunity. J. Immunol. 163, 5211–5218 (1999).

    CAS  PubMed  Google Scholar 

  38. Steitz, J., Bruck, J., Lenz, J., Knop, J. & Tuting, T. Depletion of CD25+CD4+ T cells and treatment with tyrosinase-related protein 2–transduced dendritic cells enhance the interferon α–induced, CD8+ T-cell-dependent immune defense of B16 melanoma. Cancer Res. 61, 8643–8646 (2001).

    CAS  PubMed  Google Scholar 

  39. Piccirillo, C.A. & Shevach, E.M. Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J. Immunol. 167, 1137–1140 (2001).

    Article  CAS  Google Scholar 

  40. van Maurik, A., Herber, M., Wood, K.J. & Jones, N.D. Cutting edge: CD4+CD25+ alloantigen-specific immunoregulatory cells that can prevent CD8+ T cell-mediated graft rejection: implications for anti-CD154 immunotherapy. J. Immunol. 169, 5401–5404 (2002).

    Article  CAS  Google Scholar 

  41. Iellem, A. et al. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4+CD25+ regulatory T cells. J. Exp. Med. 194, 847–853 (2001).

    Article  CAS  Google Scholar 

  42. Wu, M., Fang, H. & Hwang, S.T. Cutting edge: CCR4 mediates antigen-primed T cell binding to activated dendritic cells. J. Immunol. 167, 4791–4795 (2001).

    Article  CAS  Google Scholar 

  43. Tang, H.L. & Cyster, J.G. Chemokine Up-regulation and activated T cell attraction by maturing dendritic cells. Science 284, 819–822 (1999).

    Article  CAS  Google Scholar 

  44. Zhang, L. et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 348, 203–213 (2003).

    Article  CAS  Google Scholar 

  45. Bieche, I. et al. Quantification of estrogen receptor α and β expression in sporadic breast cancer. Oncogene 20, 8109–8115 (2001).

    Article  CAS  Google Scholar 

  46. Zou, W. et al. Quantification of cytokine gene expression by competitive PCR using a colorimetric assay. Eur. Cytokine Netw. 6, 257–264 (1995).

    CAS  PubMed  Google Scholar 

  47. Zou, W. et al. Macrophage-derived dendritic cells have strong Th1-polarizing potential mediated by β-chemokines rather than IL-12. J. Immunol. 165, 4388–4396 (2000).

    Article  CAS  Google Scholar 

  48. Lecoeur, H., Fevrier, M., Garcia, S., Riviere, Y. & Gougeon, M.L. A novel flow cytometric assay for quantitation and multiparametric characterization of cell-mediated cytotoxicity. J. Immunol. Methods 253, 177–187 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Y. Tang and D. Olivares for technical assistance and D. Emilie, R. Weiner and J. Puschett for support. This work was supported by the Department of Defense (OC020173), the National Cancer Institute (CA092562, CA100227), Louisiana Board of Regents (126A) and the Concern Foundation (W.Z.); National Cancer Institute P01-CA83638 (G.C.), RR00164 (X.A and A.L.); and CA97085 (L.C.).

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Correspondence to Weiping Zou.

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Supplementary information

Supplementary Table 1

Clinical characteristics of patients. (PDF 16 kb)

Supplementary Table 2

Tumor regulatory T cells predict survival. (PDF 17 kb)

Supplementary Methods (PDF 27 kb)

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Curiel, T., Coukos, G., Zou, L. et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med 10, 942–949 (2004). https://doi.org/10.1038/nm1093

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