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Dissociation of Its Opposing Immunologic Effects Is Critical for the Optimization of Antitumor CD8⁺ T-Cell Responses Induced by Interleukin 21

Authors' Affiliations: Departments of ¹ Medical Oncology and ² Biostatistics and Computational Biology, Dana-Farber Cancer Institute; ³ Department of Medicine, Brigham and Women's Hospital; and ⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts

Requests for reprints: Naoto Hirano, Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6186; Fax: 617-632-2255; E-mail: Naoto_Hirano{at}dfci.harvard.edu.

Purpose: Interleukin 21 (IL-21) is a promising new cytokine, which is undergoing clinical testing as an anticancer agent. Although IL-21 provides potent stimulation of CD8⁺ T cells, it has also been suggested that IL-21 is immunosuppressive by counteracting the maturation of dendritic cells. The dissociation of these two opposing effects may enhance the utility of IL-21 as an immunotherapeutic. In this study, we used a cell-based artificial antigen-presenting cell (aAPC) lacking a functional IL-21 receptor (IL-21R) to investigate the immunostimulatory properties of IL-21.

Experimental Design: The immunosuppressive activity of IL-21 was studied using human IL-21R⁺ dendritic cells. Antigen-specific CD8⁺ T cells stimulated with human cell–based IL-21R^-aAPC were used to isolate the T-cell immunostimulatory effects of IL-21. The functional outcomes, including phenotype, cytokine production, proliferation, and cytotoxicity were evaluated.

Results: IL-21 limits the immune response by maintaining immunologically immature dendritic cells. However, stimulation of CD8⁺ T cells with IL-21R^- aAPC, which secrete IL-21, results in significant expansion. Although priming in the presence of IL-21 temporarily modulated the T-cell phenotype, chronic stimulation abrogated these differences. Importantly, exposure to IL-21 during restimulation promoted the enrichment and expansion of antigen-specific CD8⁺ T cells that maintained IL-2 secretion and gained enhanced IFN- secretion. Tumor antigen-specific CTL generated in the presence of IL-21 recognized tumor cells efficiently, demonstrating potent effector functions.

Conclusions: IL-21 induces opposing effects on antigen-presenting cells and CD8⁺ T cells. Strategic application of IL-21 is required to induce optimal clinical effects and may enable the generation of large numbers of highly avid tumor-specific CTL for adoptive immunotherapy.