IL-12p70 and IL-18 gene-modified dendritic cells loaded with tumor antigen-derived peptides or recombinant protein effectively stimulate specific Type-1 CD4+ T-cell responses from normal donors and melanoma patients in vitro.
Although CD4(+) Type-1T helper (Th1) cells secreting interferon-gamma (IFN-gamma) appear to play an essential role in promoting durable antitumor immunity, we have previously shown that patients with cancer exhibit dysfunctional Th1-type responses against epitopes derived from tumor antigens, such as MAGE-A6. Here, we engineered human dendritic cells (DCs) to secrete high levels of the IFN-gamma-inducing cytokines, interleukin (IL)-12p70 and IL-18, via recombinant adenoviral infection to generate an in vitro stimulus capable of promoting previously deficient patient Th1-type responses. Dendritic cells co-infected with Ad.IL-12 and Ad.IL-18 (DC.IL-12/18) were more effective at stimulating MAGE-A6-specific Th1-type CD4(+) T-cell responses than DCs infected with either of the cytokine vectors alone, control Ad.Psi5 virus or uninfected DCs. Furthermore, we show that DC.IL-12/18 loaded with recombinant MAGE-A6 protein (rMAGE) and used as in vitro stimulators promote Th1-type immunity that is frequently directed against multiple MAGE-A6-derived epitopes. The superiority of DC.IL-12/18-based stimulations in melanoma patients was independent of disease stage or current disease status. Based on these results, we believe this modality may prove clinically useful as a vaccine platform to promote the recovery of tumor antigen-specific, Th1-type CD4(+) T-cell responses in patients with cancer.
Vujanovic
L
L
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Ranieri
E
E
Gambotto
A
A
Olson
W C
WC
Kirkwood
J M
JM
Storkus
W J
WJ
D000256:Adenoviridae; D000951:Antigens, Neoplasm / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines; D003713:Dendritic Cells / Q000276:immunology*; D005822:Genetic Vectors; D006801:Humans; D066298:In Vitro Techniques; D018664:Interleukin-12 / Q000235:genetics; D020382:Interleukin-18 / Q000235:genetics; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D009363:Neoplasm Proteins / Q000235:genetics*; D011994:Recombinant Proteins; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D018417:Th1 Cells
D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D020382:Interleukin-18; C095203:MAGEA6 protein, human; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; D018664:Interleukin-12