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Immunological and Antitumor Effects of IL-23 as a Cancer Vaccine Adjuvant¹

Willem W. Overwijk^2,*, Karin E. de Visser^3,*, Felicia H. Tirion^*, Laurina A. de Jong^*, Thijs W. H. Pols^*, Yme U. van der Velden^*, Jasper G. van den Boorn^*, Anna M. Keller^*, Wim A. Buurman, Marc R. Theoret, Bianca Blom^4,*, Nicholas P. Restifo, Ada M. Kruisbeek^5,*, Robert A. Kastelein and John B. A. G. Haanen^*

^* Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of General Surgery, University Maastricht, Maastricht, The Netherlands; National Cancer Institute, National Institutes of Health, Bethesda, MD 20892; and DNAX Research Institute, Palo Alto, CA 93404

The promising, but modest, clinical results of many human cancer vaccines indicate a need for vaccine adjuvants that can increase both the quantity and the quality of vaccine-induced, tumor-specific T cells. In this study we tested the immunological and antitumor effects of the proinflammatory cytokine, IL-23, in gp100 peptide vaccine therapy of established murine melanoma. Neither systemic nor local IL-23 alone had any impact on tumor growth or tumor-specific T cell numbers. Upon specific vaccination, however, systemic IL-23 greatly increased the relative and absolute numbers of vaccine-induced CD8⁺ T cells and enhanced their effector function at the tumor site. Although IL-23 specifically increased IFN- production by tumor-specific T cells, IFN- itself was not a primary mediator of the vaccine adjuvant effect. The IL-23-induced antitumor effect and accompanying reversible weight loss were both partially mediated by TNF-. In contrast, local expression of IL-23 at the tumor site maintained antitumor activity in the absence of weight loss. Under these conditions, it was also clear that enhanced effector function of vaccine-induced CD8⁺ T cells, rather than increased T cell number, is a primary mechanism underlying the antitumor effect of IL-23. Collectively, these results suggest that IL-23 is a potent vaccine adjuvant for the induction of therapeutic, tumor-specific CD8⁺ T cell responses.

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