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

Abstract

We investigated the role of tumor cell-derived GM-CSF in recruitment and tumoricidal activation of tissue macrophages. Transfection of the murine GM-CSF gene into KM12SM human colon cancer cells decreased the tumorigenicity of transfected cells and nontransfected bystander colon cancer cells in nude mice. Sequential tissue sections from sites injected with high GM-CSF-producing tumor cells (but not from nontransfected or low GM-CSF-producing cells) demonstrated a dense infiltration of polymorphonuclear cells (PMN), followed by infiltration of macrophages, which correlated with expression of the macrophage-inflammatory protein-1α and the monocyte chemoattractant protein-1 (MCP-1) in mouse PMN and macrophages. GM-CSF-producing KM12SM cells were highly sensitive to lysis by mouse macrophages and also increased macrophage-mediated lysis of bystander nontransfected KM12SM cells. The incubation of macrophages with GM-CSF induced expression of the CD11b surface adhesion molecule, which was associated with increased attachment to tumor cells. All KM12SM cells were sensitive to macrophage-mediated lysis in the presence of rGM-CSF and recombinant MCP-1. Collectively, the results demonstrate that tumor cell-derived GM-CSF stimulates PMN and macrophages to secrete macrophage-inflammatory protein-1α and MCP-1, which triggers recruitment of mononuclear cells, induces expression of adhesion molecules on macrophages, and enhances contact-dependent cytolysis of tumor cells.

Mac-1 (CD11b/CD18) is crucial for effective Fc receptor–mediated immunity to melanoma

“…Since Mac-1 deficiency abrogates neutrophil ADCC capacity, 25 we hypothesize that Ab-reliant melanoma destruction results from cross-talk between neutrophils and other cytotoxic effectors. 47,51 Although we did not observe apparent macrophage infiltration into tumor sites, Mac-1-deficient macrophages are capable of killing tumor cells, in contrast to neutrophils. This likely reflects differences in cytolytic effector mechanisms between these types of phagocytic cells.…”

“…Consistent with our data, G-CSF transduction of adenocarcinoma results in antitumor activity mediated by neutrophils. 42,43 Furthermore, phagocytes have been shown to infiltrate tumor sites including melanoma, [44][45][46][47] and neutrophils have earlier been found important for tumor cell elimination in vivo. 8,43,[48][49][50] Ab-mediated protection against melanoma was reduced by approximately 50% in Mac-1 Ϫ/Ϫ mice, pointing to a Mac-1-independent pathway in FcR-mediated tumor cytotoxicity.…”

Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis

“…In one hand, CCL2 can potentiate both the innate and acquired immune responses that inhibit tumor growth through recruiting immune cells to enter the tumors and enhance contact-dependent cytolysis of tumor cells (33)(34)(35). On other hand, CCL2 induces macrophage accumulation and cyclooxygenase-2 expression promoting inflammation in colorectal adenoma epithelium, which has been reported to promote tumor progression in autocrine and paracrine fashions (36)(37)(38)(39).…”

Microarray Analysis of Lipopolysaccharide Potentiation of Trovafloxacin-Induced Liver Injury in Rats Suggests a Role for Proinflammatory Chemokines and Neutrophils

“…Treatment with GM-CSF causes PMN accumulation (Shinohara et al, 2000), and PMN have been implicated in several liver injury processes, including endotoxemia, hepatic ischemia-reperfusion, and sepsis (Jaeschke et al, 1990(Jaeschke et al, , 1991Hewett et al, 1993;Molnar et al, 1997). During endotoxemic reactions, PMN can cause hepatotoxicity in part through generation of reactive oxygen species (Gujral et al, 2004).…”