Macrophage inflammatory protein 3 alpha transgene attracts dendritic cellsto established murine tumors and suppresses tumor growth

Dendritic cells (DCs) are powerful antigen-presenting cells that function a s the principal activators of T cells. Sitter: the human CC chemokine, macr ophage inflammatory protein 3 alpha (MIP-3 alpha), is chemotactic for DCs i n vitro, we hypothesized that adenovirus-mediated gene transfer of MIP-3 al pha (AdMIP-3 alpha) to tumors might induce local accumulation of DCs and in hibit growth of preexisting tumors. AdMIP-3 alpha directed expression of mR NA and protein in vitro, and the supernatant of A549 cells infected with Ad MIP-3 alpha was chemotactic for DCs. In vivo, injection of AdMIP-3 alpha in to subcutaneous tumors resulted in local expression of the MIP-3 alpha cDNA and in the local accumulation of DCs. In four syngeneic tumor models, grow th of established tumors was significantly inhibited compared with untreate d tumors or tumors injected with control vector, and in all but the poorly immunogenic LLC carcinoma model, this treatment increased survival advantag e of the preexisting tumors. In all four tumor models, intratumoral injecti on of AdMIP-3 alpha induced the local accumulation of CD8b.2(+) cells and e licited tumor-specific cytotoxic T-lymphocyte activity, and adoptive transf er of splenocytes of animals receiving this treatment protected against a s ubsequent challenge with the identical tumor cells. In wild-type but not in CD8-deficient mice, AdMIP-3 alpha inhibited the growth of tumors. Finally AdMIP-3 alpha also inhibited the growth of distant tumors. This strategy ma y be useful for enlisting the help of DCs to boost anti-tumor immunity agai nst local and metastatic tumors without the necessity of ex vivo isolation and manipulation of DCs.