Gene therapy for gastrointestinal tumors using antigen presenting cells activated with gene transfer

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We examined whether professional antigen presenting cells (dendritic cells) could be activated by the expression of CD40 ligand (CD40L) gene on tumors and antitumor immunity was subsequently induced. We retrovirally transduced tumors with the CD40L gene and established CD40L-expressed tumors whose MHC class I expression remained the same as that of parent tumors. Inoculation of the transduced cells into syngeneic mice revealed that growth of CD40L-expressed tumors was significantly retarded compared with that of parent tumors. Some of the mice completely rejected the CD40L-expressed tumors and the mice developed antigen-specific protective immunity. When nude mice were inoculated with the CD40L-expressed tumors, the growth was not different from that of parent tumors. In vitro culture of the CD40L-expressed tumors and bone marrow-derived dendritic cells showed that the cluster formation between dendritic cells and the CD40L-expressed but not parent tumors. The expression of MHC class II and activation marker CD86 on dendritic cells was upregulated after the coculture with CD40L-expressed but not parent tumors. The activated dendritic cells secreted IL-12, IL-18, IL-23 and Mig. These data collectively suggest that CD40L on tumors can activate dendritic cells through CD40/CD40L interaction and induce the expression of cytokines and chemokines, which play a crucial role in the generation of T cell-mediated antitumor effects.