Immune deviation and Fas-mediated deletion limit antitumor activity after multiple dendritic cell vaccinations in mice

Genetic immunization with a single injection of dendritic cells (DCs) expre ssing a model melanoma antigen generates antigen-specific, MHC-restricted, protective immune responses. After initiating the immune response, addition al vaccinations may increase the protection or conversely downregulate the immune response. Groups of mice were vaccinated several times with DCs tran sduced with the MART-1 gene, and the antitumor protection was compared with that of mice receiving a single vaccination. C3H mice had poorer protectio n from a syngeneic MART-expressing tumor challenge,vith multiple vaccinatio ns, This was accompanied by lower levels of splenic CTL effecters and a shi ft from a type 1 to a type 2 cytokine profile, On the contrary, multiple va ccinations in C57BL/6 mice generated greater in vivo antitumor protection w ith no decrease in splenic CTLs and no cytokine shift. Antiadenoviral humor al or cellular immune responses did not seem to contribute to these effects . When studies were performed in Fas receptor-negative C3H.(lpr) mice, the adverse effect of multiple vaccinations disappeared, and there was no cytok ine shift pattern. In conclusion, C3H mice but not C57BL/6 mice receiving m ultiple vaccinations with DCs expressing the MART-1 tumor antigen show decr eased protection associated with deviation from a type 1 to a type 2 cytoki ne response attributable to a Fas-receptor mediated clearance of antigen-sp ecific IFN-gamma-producing cells.