Introduction: The tumor-associated macrophage (TAM) is at the front line of the host's defense against malignancy and provides an attractive target for immune-modulatory therapy. However, factors present within the tumor microenvironment can alter macrophage phenotype, preventing its cytotoxic activity and reducing its susceptibility to interferon-gamma and lipopolysaccharide-mediated stimulation.
Methods: Macrophages were isolated from subcutaneous B16 melanoma tumors implanted in C57 BL/6 mice. Wound macrophages were harvested from subcutaneously-implanted PVA sponges, and resting peritoneal macrophages were harvested by peritoneal lavage. Gene expression was analyzed using an Atlas cDNA array (Clontech, Mountain View, CA).
Results: TAM demonstrated a pattern of gene expression distinct from both wound and peritoneal macrophage. There is an increase in proliferation-associated genes and in genes encoding the ultrastructural proteins cofillin, zyxin, and vimentin more commonly associated with fibroblast-like cells. In addition, an observed decrease in expression of the CD14 gene, and increase in inhibitory pathways including osteopontin and its receptor CD44, the inositol 1,4,5-triphosphate receptor, and the receptors for interleukin-4 and granulocyte monocyte-colony stimulating factor could explain the resistance of TAM to lipopolysaccharide-mediated stimulation. There was also a significant decrease in the expression of the interferon-gamma second messenger, IRF-1.
Conclusions: This study has identified a number of pathways involved in the suppression of TAM function. Targeting of these pathways may allow for the generation of more effective immune-modulatory anti-neoplastic therapy.