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Immune Deviation and Fas-mediated Deletion Limit Antitumor Activity after Multiple Dendritic Cell Vaccinations in Mice¹

Divisions of Surgical Oncology [A. R., L. H. B., B. H., V. B. D., W. S. M., A. K., K. J. A., M. L., S. N. A., J. S. E.], Hematology-Oncology [A. R., J. A. G.], and Experimental Radiation Oncology [W. H. M.], University of California at Los Angeles, Los Angeles, California 90095

Genetic immunization with a single injection of dendritic cells (DCs) expressing a model melanoma antigen generates antigen-specific, MHC-restricted, protective immune responses. After initiating the immune response, additional vaccinations may increase the protection or conversely downregulate the immune response. Groups of mice were vaccinated several times with DCs transduced with the MART-1 gene, and the antitumor protection was compared with that of mice receiving a single vaccination. C3H mice had poorer protection from a syngeneic MART-1-expressing tumor challenge with multiple vaccinations. This was accompanied by lower levels of splenic CTL effectors and a shift from a type 1 to a type 2 cytokine profile. On the contrary, multiple vaccinations in C57BL/6 mice generated greater in vivo antitumor protection with no decrease in splenic CTLs and no cytokine shift. Antiadenoviral humoral 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 cytokine shift pattern. In conclusion, C3H mice but not C57BL/6 mice receiving multiple vaccinations with DCs expressing the MART-1 tumor antigen show decreased protection associated with deviation from a type 1 to a type 2 cytokine response attributable to a Fas-receptor mediated clearance of antigen-specific IFN--producing cells.

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