ICAM-1 suppresses tumor metastasis by inhibiting macrophage M2 polarization through blockade of efferocytosis

Abstract

Efficient clearance of apoptotic cells (efferocytosis) can profoundly influence tumor-specific immunity. Tumor-associated macrophages are M2-polarized macrophages that promote key processes in tumor progression. Efferocytosis stimulates M2 macrophage polarization and contributes to cancer metastasis, but the signaling mechanism underlying this process is unclear. Intercellular cell adhesion molecule-1 (ICAM-1) is a transmembrane glycoprotein member of the immunoglobulin superfamily, which has been implicated in mediating cell–cell interaction and outside-in cell signaling during the immune response. We report that ICAM-1 expression is inversely associated with macrophage infiltration and the metastasis index in human colon tumors by combining Oncomine database analysis and immunohistochemistry for ICAM-1. Using a colon cancer liver metastasis model in ICAM-1-deficient (ICAM-1−/−) mice and their wild-type littermates, we found that loss of ICAM-1 accelerated liver metastasis of colon carcinoma cells. Moreover, ICAM-1 deficiency increased M2 macrophage polarization during tumor progression. We further demonstrated that ICAM-1 deficiency in macrophages led to promotion of efferocytosis of apoptotic tumor cells through activation of the phosphatidylinositol 3 kinase/Akt signaling pathway. More importantly, coculture of ICAM-1−/− macrophages with apoptotic cancer cells resulted in an increase of M2-like macrophages, which was blocked by an efferocytosis inhibitor. Our findings demonstrate a novel role for ICAM-1 in suppressing M2 macrophage polarization via downregulation of efferocytosis in the tumor microenvironment, thereby inhibiting metastatic tumor progression.

Essential role of ICAM-1 in aldosterone-induced atherosclerosis

“…As the incidence and outcomes from atherosclerotic vascular disease differ in males and females, and studies show that estrogen receptor may modulate MR regulation of ICAM-1 in endothelial cells [47], future studies are needed to explore whether this mechanism contributes to plaque formation in females. Another limitation stems from the lack of investigation of macrophages ICAM-1 expression in response to ALDO, which could also contribute to explain the pro-atherogenic effects of ALDO [48]. In fact, MR is expressed in macrophages and affects their M1/M2 polarization and cardiac infiltration [49–51].…”

Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone

“…Furthermore, activation of Stat3 by efferocytosis mediates the M2-like polarization of bone marrow macrophages (12). In vivo studies in breast and colon cancer showed that efferocytosis induced M2 polarization and metastasis, while increased cell death correlated with poorer outcomes (13,48). Moreover, the proinflammatory cytokine IL-6 induced M2-like macrophage polarization in human macrophages (49).…”

A Preclinical Model of Chronic Alcohol Consumption Reveals Increased Metastatic Seeding of Colon Cancer Cells in the Liver

“…Previous studies have reported the potential role of ICAM-1 in cancer metastasis. Clinical research on colorectal cancer has revealed a positive relation between liver metastasis and the sinusoidal expression of ICAM-1 (21); however, a recent study showed that ICAM-1 deficiency in mice accelerated liver metastasis of SL4 colon cancer cells (22). Further studies are needed to determine the role of ICAM-1 in liver metastasis under condition of alcohol consumption.…”