Macrophage inflammatory protein 3α transgene attracts dendritic cells to established murine tumors and suppresses tumor growth

Dendritic cells (DCs) are powerful antigen-presenting cells that function as the principal activators of T cells. Sitter: the human CC chemokine, macrophage inflammatory protein 3 alpha (MIP-3 alpha), is chemotactic for DCs in vitro, we hypothesized that adenovirus-mediated gene transfer of MIP-3 alpha (AdMIP-3 alpha) to tumors might induce local accumulation of DCs and inhibit growth of preexisting tumors. AdMIP-3 alpha directed expression of mRNA and protein in vitro, and the supernatant of A549 cells infected with AdMIP-3 alpha was chemotactic for DCs. In vivo, injection of AdMIP-3 alpha into subcutaneous tumors resulted in local expression of the MIP-3 alpha cDNA and in the local accumulation of DCs. In four syngeneic tumor models, growth of established tumors was significantly inhibited compared with untreated tumors or tumors injected with control vector, and in all but the poorly immunogenic LLC carcinoma model, this treatment increased survival advantage of the preexisting tumors. In all four tumor models, intratumoral injection of AdMIP-3 alpha induced the local accumulation of CD8b.2(+) cells and elicited tumor-specific cytotoxic T-lymphocyte activity, and adoptive transfer of splenocytes of animals receiving this treatment protected against a subsequent 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 may be useful for enlisting the help of DCs to boost anti-tumor immunity against local and metastatic tumors without the necessity of ex vivo isolation and manipulation of DCs.