title: Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant.
abstract: 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-gamma production by tumor-specific T cells, IFN-gamma 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-alpha. 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.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, 1105 AZ Amsterdam, The Netherlands. woverwijk@mdanderson.org
authors.forename: Willem W
authors.initials: WW
authors.lastname: Overwijk
authors.forename: Karin E
authors.initials: KE
authors.lastname: de Visser
authors.forename: Felicia H
authors.initials: FH
authors.lastname: Tirion
authors.forename: Laurina A
authors.initials: LA
authors.lastname: de Jong
authors.forename: Thijs W H
authors.initials: TW
authors.lastname: Pols
authors.forename: Yme U
authors.initials: YU
authors.lastname: van der Velden
authors.forename: Jasper G
authors.initials: JG
authors.lastname: van den Boorn
authors.forename: Anna M
authors.initials: AM
authors.lastname: Keller
authors.forename: Wim A
authors.initials: WA
authors.lastname: Buurman
authors.forename: Marc R
authors.initials: MR
authors.lastname: Theoret
authors.forename: Bianca
authors.initials: B
authors.lastname: Blom
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Restifo
authors.forename: Ada M
authors.initials: AM
authors.lastname: Kruisbeek
authors.forename: Robert A
authors.initials: RA
authors.lastname: Kastelein
authors.forename: John B A G
authors.initials: JB
authors.lastname: Haanen
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000941:Antigens / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology* / Q000494:pharmacology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000493:pharmacokinetics / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D007371:Interferon-gamma / Q000096:biosynthesis; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins / Q000008:administration & dosage / Q000276:immunology*; D051379:Mice; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D000970:Antineoplastic Agents; D019496:Cancer Vaccines; C508840:IL23A protein, human; C508841:Il23a protein, mouse; D053759:Interleukin-23; D053760:Interleukin-23 Subunit p19; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma