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 cell s (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 i nterferon-gamma (IFN-gamma) were found to markedly enhance the immunogenici ty of TAA presented by DC. While PC upregulated expression of major histoco mpatibility complex class I/II and costimulatory molecules on the surface o f DC, CD40L +/- IFN-gamma increased interleukin (IL)-12 and to a lesser ext ent, IL-15 production by DC. Additionally, lactacystin, a specific proteaso me 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-ine xperienced ("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 coul d be made more effective by the addition of proinflammatory cytokines or CD 40L +/- IFN-gamma, to improve the DC function.