Immune responsiveness in a mouse model of combined adoptive immunotherapy with NK and dendritic cells

Abstract

Objective: To determine the tumoricidal ability of combined immunotherapy of natural killer (NK) cells and dendritic cells (DCs) in a melanoma mouse model and the functions of tumor-associated effector cells. Materials and Methods: A C57BL/6 mouse model of subcutaneous melanoma and lung metastasis was established. NK cells and DCs were cultured and labeled in vitro. Varying frequencies of both NK cells and DCs were adoptively transferred into tumor-bearing mice. Tumor, liver, spleen, and lung were studied for the number and distribution of effector cells. Additionally, CD8+T cell numbers in the lung and numbers of metastatic lung nodules were determined. Results: Co-culture of NK cells and DCs might maintain and promote NK cell activity without exogenous cytokines. Both NK cells and DCs were distributed in the tumor microcirculation and parenchyma. We found significant time-dependent differences in the numbers of infiltrating NK cells and DCs (P < 0.01), which stimulated the highest frequencies of effector cells 4 h after transfer and the lowest at 12 h. Low NK cell numbers were found in the spleen, and fewer numbers were found in liver and lung. Infiltration of tumors with effector cells was greatest following mixed cell transfers as compared to single transfers, and markedly increased CD8+T cells were associated with significant decreases in lung metastases. Conclusion: NK cells and DCs adoptive immunotherapy targeted the tumor and exhibited improved therapeutic efficacy as compared to that of the cells given alone. This strategy could induce tumorigenic immunological memory and suggests that mixed NK cells and DCs adoptive immunotherapy offers therapeutic options against cancer.