Proinflammatory Cytokines and CD40 Ligand Enhance Cross-Presentation and Cross-Priming Capability of Human Dendritic Cells Internalizing Apoptotic Cancer Cells.
SUMMARY: 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.
Hoffmann
Thomas K.
TK
University of Pittsburgh Cancer Institute, Department of Surgery and Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, U.S.A.
Meidenbauer
Norbert
N
Müller-Berghaus
Jan
J
Storkus
Walter J.
WJ
Whiteside
Theresa L.
TL