Immunotherapy Of Tumors With Recombinant Adenovirus Encoding Macrophage Inflammatory Protein 3β

Mip3β(Macrophage inflammatory protein 3β)/ELC(EBI-1 Ligand Chemokine)/CCL19 is a CC chemokine identified via bioinformatics. Its mRNA is detected in thymus and secondary lymphoid organs. Mip3β chemoattracts T cells, dendritic cells(DC), NK cells and macrophage progenitor cells, and may be involved in the interactions between DC and T cells in secondary lymphoid tissues. Based on the capacity of Mip3β to induce specific homing of most lymphoid cells and DC, we hypothesized that the intratumoral administration of Mip3β might induce or enhance a specific anti-tumor response. To test this concept, we constructed a replication-deficient recombinant adenovirus encoding mouse Mip3β (Ad-Mip3β) and control vectors (Ad-Null) in an E.Coli-based homologous recombination system. The antitumor efficacy of Ad-Mip3β was evaluated in both murine lung cancer model (LL/2) and CT26 colon carcinoma model (CT26). We found the intratumoral administration of Ad-Mip3p (5 × 10~8PFU per mouse at an interval of every three days for a total of 6 doses) could induceeffective anti-tumor immune response. There was apparent protection from tumor growth in Ad-Mip3β-treated mice. The survival of the mice injected with Ad-Mip3β was also significantly greater than that of Ad-Null-treated mice or PBS-treated mice. MHC class I-dependent CD8~+ CTL activity was found in T cells isolated from spleens of mice treated with Ad-Mip3β. There were also found increased IFN-γ secreting cells in spleen cells of Ad-Mip3β-treated mice. Furthermore, depletion of CD8~+T lymphocytes showed apparent abrogation of the anti-tumor activity in vivo, whereas the depletion of CD4~+ T lymphocytes showed partial abrogation of the antitumor activity. The adoptive transfer of CD4-depleted (CD8~+) or CD8-depleted (CD4~+) T cells isolated from mice treated with Ad-Mip3p showed the anti-tumor activity. Immunohistochemical staining revealed that Ad-Mip3β-treated mice exhibited apparent lymphocytes infiltration accompanied with distinct nercosis and apoptosis within the tumor tissues.Taken together, this study approved that intratumoral administration of Ad-Mip3β could induce effective antitumor immunity. These findings may provide a new strategy of tumor immunotherapy by facilitating localization of lymphocytes and DC at the site of tumor antigen and thus reversing tumor-mediated immune suppression.