Proinflammatory cytokines and CD40 ligand enhance cross-presentation and cross-priming capability of human dendritic cells internalizing apoptotic cancer cells.
Human monocyte-derived dendritic cells (DC) can ingest apoptotic tumor cells (ATC) and present tumor-associated antigens (TAA) to T cells, leading to the generation of tumor-specific cytotoxic effector cells (Cancer Res 2000;60:3542-9). To further augment antitumor effector cell responses, attempts were made to modify antigen presentation and cross-priming of T cells by DC fed with ATC. Proinflammatory cytokines (PC), CD40 ligand (CD40L) and/or interferon-gamma (IFN-gamma) were found to markedly enhance the immunogenicity of TAA presented by DC. While PC upregulated expression of major histocompatibility complex class I/II and costimulatory molecules on the surface of DC, CD40L +/- IFN-gamma increased interleukin (IL)- 12 and to a lesser extent, IL-15 production by DC. Additionally, lactacystin, a specific proteasome inhibitor, significantly abrogated the effects of IFN-gamma and, in part, also those of CD40L or PC. The ability of DC + ATC to cross-prime TAA-inexperienced ("naive") T cells was significantly enhanced by PC and CD40L or CD40L + IFN-gamma, but not by IFN-gamma alone. These results indicate that future vaccines for patients with cancer incorporating DC fed with ATC could be made more effective by the addition of proinflammatory cytokines or CD40L +/- IFN-gamma to improve the DC function.
University of Pittsburgh Cancer Institute, Pennsylvania 15213-2582, USA.
T K
TK
Hoffmann
N
N
Meidenbauer
J
J
Müller-Berghaus
W J
WJ
Storkus
T L
TL
Whiteside
D000906:Antibodies / Q000494:pharmacology; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000276:immunology; D017209:Apoptosis; D023201:CD40 Ligand / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell; D016207:Cytokines / Q000494:pharmacology*; D003713:Dendritic Cells / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000276:immunology; D006258:Head and Neck Neoplasms; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D009369:Neoplasms / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014407:Tumor Cells, Cultured
D000906:Antibodies; D000951:Antigens, Neoplasm; D016207:Cytokines; D015789:HLA-A2 Antigen; D015395:Histocompatibility Antigens Class I; D023201:CD40 Ligand; D007371:Interferon-gamma