Antitumor effects of combined granulocyte macrophage colony stimulating factor and macrophage inflammatory protein-3 alpha plasmid DNA

Abstract

Dendritic cells (DC) are critical for priming adaptive immune responses to foreign antigens. However, the feasibility of harnessing these cells in vivo to optimize the antitumor effects has not been fully explored. The authors investigated a novel therapeutic approach that involves delivering synergistic signals that both recruit and expand DC populations at sites of intratumoral injection. More specifically, the authors examined whether the co-administration of plasmids encoding the chemokine macrophage inflammatory protein-3 alpha (pMIP3 alpha) and plasmid encoding the granulocyte macrophage colony stimulating factor (pGM-CSF; a DC-specific growth factor) can recruit, expand and activate large numbers of DC at sites of intratumoral injection. It was found that the administration of pGM-CSF and pMIP3 alpha resulted in dramatic recruitment and expansion of DC at these sites and in draining lymph nodes. Furthermore, treatment with pGM-CSF and pMIP3 alpha generated the strongest MUC1-associated CD8+ T-cell immune responses in draining lymph nodes and in tumors, produced the greatest antitumor effects and enhanced survival rates more than pcDNA3.1, pGM-CSF alone and pMIP3 alpha alone. It was also found that pGM-CSF plus pMIP3 alpha generated the strongest MUC1-associated CD4+ T-cell immune responses in draining lymph nodes and in tumors. The findings of the present study suggest that the recruitment and activation of DC in vivo due to the synergistic actions of pGM-CSF and pMIP3 alpha presents a potentially feasible means of controlling immunogenic malignancies and provides a basis for the development of novel immunotherapeutic treatments. (Cancer Sci 2010; 101: 2341-2350).