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

Nature Medicine volume 10, pages 942949 (2004) | Download Citation

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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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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.).

Author information

Affiliations

  1. Tulane University Health Science Center, New Orleans, Louisiana 70112, USA.

    • Tyler J Curiel
    • , Linhua Zou
    • , Xavier Alvarez
    • , Pui Cheng
    • , Peter Mottram
    • , Melina Evdemon-Hogan
    • , Matthew Burow
    • , Yun Zhu
    • , Shuang Wei
    • , Ilona Kryczek
    • , Ben Daniel
    • , Leann Myers
    • , Andrew Lackner
    •  & Weiping Zou
  2. Division of Gynecologic Oncology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.

    • George Coukos
    • , Jose R Conejo-Garcia
    •  & Lin Zhang
  3. Baylor University Medical Center, Dallas, Texas 75249, USA.

    • Alan Gordon
  4. Division of Oncology, University of Washington, Seattle, Washington 98195, USA.

    • Mary L Disis
    •  & Keith L Knutson
  5. Department of Dermatology, Johns Hopkins University, Baltimore, Maryland 21287, USA.

    • Lieping Chen

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The authors declare no competing financial interests.

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Correspondence to Weiping Zou.

Supplementary information

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  1. 1.

    Supplementary Table 1

    Clinical characteristics of patients.

  2. 2.

    Supplementary Table 2

    Tumor regulatory T cells predict survival.

  3. 3.

    Supplementary Methods

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DOI

https://doi.org/10.1038/nm1093

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