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Characterization of CD4⁺CD25⁺ Regulatory T Cells in Patients Treated With High-Dose Interleukin-2 for Metastatic Melanoma or Renal Cell Carcinoma

From the Tumor Immunology Laboratory, Department of Surgery and Biostatistics, Columbia University Medical Center, New York, NY

Address reprint requests to Howard L. Kaufman, MD, Columbia University Medical Center, 177 Fort Washington Ave, New York, NY 10032; e-mail: hlk2003{at}columbia.edu

PURPOSE: To characterize the number and functional status of CD4⁺CD25⁺ regulatory T cells (Tregs) in patients with metastatic melanoma (MM) and renal cell carcinoma (RCC) treated with high-dose bolus interleukin-2 (IL-2).

PATIENTS AND METHODS: Patients with MM or RCC treated with high-dose bolus IL-2 (600,000 IU/kg every 8 hours) at a single center provided pre- and post-treatment whole blood specimens. Peripheral blood mononuclear cells were isolated by Ficoll density gradient centrifugation, separated into cellular subsets, and analyzed by flow cytometry or used for in vitro proliferation assays.

RESULTS: Between September 2003 and July 2005 57 patients were enrolled in the study with 48 patients available for analysis (45 MM, 12 RCC). Tregs were defined as CD4⁺CD25^hi T cells, and this subset was significantly elevated in the cancer patients compared with normal donors (7.75% v 2.24%). The CD4⁺CD25^hi T-cell pool in the patients constitutively expressed intracellular FoxP3, CTLA-4, and produced high amounts of IL-10. The Tregs were CCR7⁺ with 50% representing naïve and 50% central-memory T cells. The cells were functionally suppressive in mixed in vitro proliferation assays. Following IL-2 administration, the number and frequency of Tregs increased in patients with progressive disease but returned to normal levels in patients with objective clinical responses.

CONCLUSION: The number of Tregs, defined as CD4⁺CD25^hi T cells is increased in patients with MM and RCC. High-dose IL-2 resulted in a significant decrease of Tregs in those patients achieving an objective clinical response to IL-2 therapy.

Supported by Grant No. RO1 93696 from the National Institutes of Health and the Chiron Corporation.

Presented in part at the Masir Congress on Measurement of Antigen-Specific Immune Responses, Courmayeur, Italy, January 26-29, 2005 and at the 58th Annual Cancer Symposium of the Society of Surgical Oncology, Atlanta, GA, March 3-5, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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