Immunological and antitumor effects of IL-23 as a cancer vaccine adjuvant.
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.
Overwijk
Willem W
WW
Division of Immunology, The Netherlands Cancer Institute, 1105 AZ Amsterdam, The Netherlands. woverwijk@mdanderson.org
de Visser
Karin E
KE
Tirion
Felicia H
FH
de Jong
Laurina A
LA
Pols
Thijs W H
TW
van der Velden
Yme U
YU
van den Boorn
Jasper G
JG
Keller
Anna M
AM
Buurman
Wim A
WA
Theoret
Marc R
MR
Blom
Bianca
B
Restifo
Nicholas P
NP
Kruisbeek
Ada M
AM
Kastelein
Robert A
RA
Haanen
John B A G
JB
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
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