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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 942–949 (2004)Cite this article

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.

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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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Authors and Affiliations

  1. Tulane University Health Science Center, New Orleans, 70112, Louisiana, 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, 19104, Pennsylvania, USA

    George Coukos, Jose R Conejo-Garcia & Lin Zhang

  3. Baylor University Medical Center, Dallas, 75249, Texas, USA

    Alan Gordon

  4. Division of Oncology, University of Washington, Seattle, 98195, Washington, USA

    Mary L Disis & Keith L Knutson

  5. Department of Dermatology, Johns Hopkins University, Baltimore, 21287, Maryland, USA

    Lieping Chen

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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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