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Interleukin-21 Augments the Efficacy of T-Cell Therapy by Eliciting Concurrent Cellular and Humoral Responses

Departments of ¹ Surgery and ² Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan; ³ Shiga University of Medical Science, Shiga, Japan; ⁴ PLA General Hospital, Beijing, People's Republic of China; and ⁵ ZymoGenetics, Inc., Seattle, Washington

Requests for reprints: Qiao Li, Department of Surgery, University of Michigan Medical Center, 1520 MSRB-1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0666. Phone: 734-615-1977; Fax: 734-763-4135; E-mail: qiaoli{at}umich.edu.

Key Words: T Cells • B Cells • Cytokine • Antibody • Cancer Immunotherapy

Interleukin (IL)-21 modulates T-cell–associated, B-cell–associated, and natural killer cell–associated immunity. However, the potential of IL-21 to simultaneously stimulate cellular and humoral antitumor responses and the mechanisms involved have not yet been adequately explored. In this report, we examined the immune-modulating effect of IL-21 when used in vitro and its adjuvant effects when administrated concomitantly with T-cell transfer for cancer therapy. Use of IL-21 in concert with IL-2 in culture up-regulated both type 1 and type 2 cytokine production of activated tumor-draining lymph node cells and enhanced their therapeutic efficacy. Administration of IL-21 and IL-2 as an adjuvant to T-cell transfer resulted in simultaneously elicited cellular and humoral responses. This concurrent response has led to effective regression of established pulmonary metastatic tumors and s.c. tumors. T-cell transfer plus IL-21/IL-2 administration conferred systemic immunity to the treated hosts. This was evident by the induction of protective immunity against tumor rechallenge, expansion of memory T cells, and significantly elevated serum levels of IFN and IL-10. Furthermore, we observed significantly enhanced tumor-associated antibody response after T-cell + IL-2 + IL-21 therapy. Cytotoxic antibody subclass IgG2b increased strikingly in the sera of treated animals; they bound specifically to MCA205 tumor cells, and such immune sera mediated tumor cell lysis in the presence of complement. Use of B-cell–deficient mice provided direct evidence that humoral responses contribute to T-cell + IL-2 + IL-21–elicited antitumor immunity. Collectively, these findings provide a rationale to evaluate the use of IL-21 in T-cell therapy of human cancers. [Cancer Res 2008;68(11):4431–41]