Induction of chemokine secretion and enhancement of contact-dependent macrophage cytotoxicity by engineered expression of granulocyte-macrophage colony-stimulating factor in human colon cancer cells

We investigated the role of tumor cell-derived GM-CSF in recruitment and tu moricidal activation of tissue macrophages, Transfection of the murine GM-C SF gene into KM12SM human colon cancer cells decreased the tumorigenicity o f transfected cells and nontransfected bystander colon cancer cells in nude mice. Sequential tissue sections from sites injected with high GM-CSF-prod ucing tumor cells (but not from nontransfected or low GM-CSF-producing cell s) demonstrated a dense infiltration of polymorphonuclear cells (PMN), foll owed by infiltration of macrophages, which correlated with expression of th e macrophage-inflammatory protein-1 alpha and the monocyte chemoattractant protein-1 (MCP-1) in mouse PMN and macrophages, GM-CSF-producing KM12SM cel ls were highly sensitive to lysis by mouse macrophages and also increased m acrophage-mediated lysis of bystander nontransfected KM12SM cells, The incu bation of macrophages with GM-CSF induced expression of the CD11b surface a dhesion molecule, which was associated,vith increased attachment to tumor c ells. All KM12SM cells were sensitive to macrophage-mediated lysis in the p resence of rGM-CSF and recombinant MCP-1, Collectively, the results demonst rate that tumor cell-derived GM-CSF stimulates PMN and macrophages to secre te macrophage-inflammatory protein-1 alpha and MCP-1, which triggers recrui tment of mononuclear cells, induces expression of adhesion molecules on mac rophages, and enhances contact-dependent cytolysis of tumor cells.