Dendritic cells stimulated with cytidine-phosphate-guanosine oligodeoxynucleotides and interferon-α-expressing tumor cells effectively reduce outgrowth of established tumors in vivo

Abstract

Dendritic cells (DC) are potent antigen-presenting cells that elicit immune responses to foreign antigens. We have previously demonstrated the synergistic effects of cytidine-phosphate-guanosine (CpG) oligodeoxynucleotides (ODN) and interferon (IFN)-α on DC maturation in vitro. In the present study, the antitumor effects of DC preincubated with IFN-α gene-overexpressing murine colorectal cancer MC38 cells (MC38-IFN-α) and CpG ODN were evaluated in a poorly immunogenic murine cancer system. When we injected DC preincubated with MC38-IFNα and CpG ODN subcutaneously to mice bearing MC38 wild-type tumors, the outgrowth of the established parental tumors was suppressed significantly compared with that following administration of DC with MC38-IFN-α (P = 0.008). All mice injected with DC preincubated with MC38-IFN-α and CpG ODN rejected a subsequent parental tumor challenge. Immunohistochemical and flow cytometric analyses showed that CD4+, CD8+, and NK1.1+ cells markedly infiltrated the established tumors of mice treated with DC preincubated with MC38-IFN-α and CpG ODN. From the results in immune cell-depleted mice, CD4+ and asialo-GM-1+ cells seemed to contribute to the antitumor effects induced by the combination DC therapy. Furthermore, non-specific cytolysis was detected when splenocytes of mice inoculated with DC preincubated with MC38-IFNα and CpG ODN were used as effector cells. Using an interleukin (IL)-12-neutralizing antibody it was suggested that IL-12 stimulates natural killer cells and contributes in part to the antitumor effects induced by DC incubated with CpG ODN and IFN-α. As DC-based immunotherapy with CpG ODN and IFN-α-expressing tumor cells induces a potent antitumor immune response, it should be considered for clinical application. © 2008 Japanese Cancer Association.