Dendritic cells (DCs) are powerful antigen-presenting cells that function as the principal activators of T cells. Since the human CC chemokine, macrophage inflammatory protein 3α (MIP-3α), is chemotactic for DCs in vitro, we hypothesized that adenovirus-mediated gene transfer of MIP-3α (ΑdMIP-3α) to tumors might induce local accumulation of DCs and inhibit growth of preexisting tumors. AdMIP-3α directed expression of mRNA and protein in vitro, and the supernatant of A549 cells infected with AdMIP-3α was chemotactic for DCs. In vivo, injection of AdMIP-3α into subcutaneous tumors resulted in local expression of the MIP-3α 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-3α 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-3α inhibited the growth of tumors. Finally, AdMIP-3α 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.
Toshiaki Fushimi, Akira Kojima, Malcolm A.S. Moore, Ronald G. Crystal