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CD4⁺CD25^high T Cells Are Enriched in the Tumor and Peripheral Blood of Prostate Cancer Patients¹

Ashley M. Miller^2,*, Kajsa Lundberg^*, Volkan Özenci^*, Alison H. Banham, Magnus Hellström, Lars Egevad and Pavel Pisa^*,

^* Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Department of Urology, and Department of Oncology and Pathology, Karolinska Institute, Stockholm, Sweden; and Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom

In this study, we investigated whether CD4⁺CD25^high regulatory T cells (Treg) are increased in the tumor tissue and peripheral blood of early-stage prostate cancer patients undergoing prostatectomy. We show that the prevalence of CD4⁺CD25^high T cells inside the prostate was significantly higher in the tumor compared with benign tissue from the same prostate. Furthermore, the frequency of CD4⁺CD25^high T cells in peripheral blood was significantly higher in prostate cancer patients compared with normal donors. A proportion of the CD4⁺CD25^high T cells was also shown to be glucocorticoid-induced TNF receptor, ICOS, and FOXP3 positive. Moreover, CD4⁺CD25⁺ T cells from blood and supernatants from cultured prostate tumor tissue samples exhibited immunosuppressive function in vitro. Furthermore, supernatants from cultured prostate tissue samples and prostate cancer ascites fluid induced migration of CD4⁺CD25⁺ T cells and were shown to contain the regulatory T cell chemokine CCL22 by ELISA. Our findings indicate that Tregs are an important cellular component of early-stage prostate tumors, and thus new therapeutic strategies aimed at inhibition or depletion of Tregs may improve prostate cancer immunotherapy.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported partly by grants from the Cancer Society in Stockholm, the Swedish Cancer Society, Karolinska Institute Funds, NordForsk Motility Grant 040226, EU 6-FP "ALLOSTEM" (LSHB-CT-2004-503319), EU 6-FP "ENACT," and U.S. Department of Defense Prostate Cancer Research Program (PC030958). A.H.B. is supported by the Leukemia Research Fund. A.M.M. is the recipient of a scholarship from Stockholm’s Odd Fellow-Logers.

² Address correspondence and reprint requests to Dr. Ashley M. Miller, Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Karolinska Institute, Stockholm, Sweden. E-mail address: Ashley.Miller{at}ki.se

³ Abbreviations used in this paper: PC, prostate cancer; Treg, regulatory T cell; GITR, glucocorticoid-induced TNF receptor; TIL, tumor-infiltrating lymphocyte; SDF-1, stromal cell-derived factor 1.

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