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Interleukin-2 Administration Alters the CD4⁺FOXP3⁺ T-Cell Pool and Tumor Trafficking in Patients with Ovarian Carcinoma

Departments of ¹ Surgery, ² Biostatistics, and ³ Medicine, University of Michigan, Ann Arbor, Michigan; ⁴ Magee-Womens Hospital, University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania; and ⁵ Section of Gynecologic Oncology, Tulane University, New Orleans, Louisiana

Requests for reprints: Weiping Zou, University of Michigan School of Medicine, C560B MSRB II, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0669. Phone: 734-615-5554; Fax: 734-763-0143; E-mail: wzou{at}umich.edu.

Interleukin (IL)-2 is used in the immunotherapy of patients with certain cancer and HIV infection. IL-2 treatment reliably results in 16% to 20% objective clinical response rate in cancer patients, with significant durability of responses in selected patients. However, the mechanisms of therapeutic activity in responding versus nonresponding patients remain poorly understood. CD4⁺CD25⁺FOXP3⁺ regulatory T (Treg) cells contribute to immunosuppressive networks in human tumors. We treated 31 ovarian cancer patients with IL-2. We show that administration of IL-2 induces the proliferation of existent Treg cells in patients with ovarian cancer. The potency of Treg cell proliferation is negatively determined by the initial prevalence of Treg cells, suggesting that Treg cells are a factor for self-controlling Treg cell proliferation. After IL-2 cessation, the number of Treg cells more efficiently dropped in clinical responders than nonresponders. Furthermore, IL-2 treatment stimulates chemokine receptor CXCR4 expression on Treg cells, enables Treg cell migration toward chemokine CXCL12 in the tumor microenvironment, and may enforce Treg cell tumor accumulation. Our findings support the concept that administration of IL-2 numerically and functionally affects the Treg cell compartment. These data provide an important insight in evaluating the clinical benefit and therapeutic prediction of IL-2 treatment in patients with cancer. [Cancer Res 2007;67(15):7487–94]