Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand.

TLDR

Both GM‑CSF and FL promote dendritic‑cell development. The study compared functional properties of DCs stimulated by GM‑CSF or FL in vivo by generating murine tumor cells that secrete high levels of each cytokine via retroviral‑mediated gene transfer. Tumor cells secreting GM‑CSF or FL markedly increased CD11c⁺ cells in spleen and tumors, but vaccination with GM‑CSF–secreting cells induced stronger antitumor immunity, a broader T‑cell cytokine response, and higher B7‑1/CD1d expression on CD8α⁻ DCs compared to FL, underscoring GM‑CSF’s superior capacity to enhance DC function in vivo and informing tumor vaccine design.

Abstract

Both granulocyte-macrophage colony-stimulating factor (GM-CSF) and flt3-ligand (FL) induce the development of dendritic cells (DCs). To compare the functional properties of DCs stimulated by these cytokines in vivo, we used retroviral-mediated gene transfer to generate murine tumor cells secreting high levels of each molecule. Injection of tumor cells expressing either GM-CSF or FL resulted in the dramatic increase of CD11c+ cells in the spleen and tumor infiltrate. However, vaccination with irradiated, GM-CSF-secreting tumor cells stimulated more potent antitumor immunity than vaccination with irradiated, FL-secreting tumor cells. The superior antitumor immunity elicited by GM-CSF involved a broad T cell cytokine response, in contrast to the limited Thl response elicited by FL. DCs generated by GM-CSF were CD8alpha- and expressed higher levels of B7-1 and CD1d than DCs cells generated by FL. Injection sites of metastatic melanoma patients vaccinated with irradiated, autologous tumor cells engineered to secrete GM-CSF demonstrated similar, dense infiltrates of DCs expressing high levels of B7-1. These findings reveal critical differences in the abilities of GM-CSF and FL to enhance the function of DCs in vivo and have important implications for the crafting of tumor vaccines.