title: 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.
authors.affiliation: 1] Beijing Anzhen Hospital, Capital Medical University, Beijing, China [2] Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing collaborative innovative research center for cardiovascular diseases, Beijing, China.
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.affiliation: 1] Beijing Anzhen Hospital, Capital Medical University, Beijing, China [2] Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing collaborative innovative research center for cardiovascular diseases, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: 1] Beijing Anzhen Hospital, Capital Medical University, Beijing, China [2] Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing collaborative innovative research center for cardiovascular diseases, Beijing, China.
authors.forename: C
authors.initials: C
authors.lastname: Piao
authors.affiliation: Second Affiliated Hospital to Nanchang University, Jiangxi 330006, China.
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.affiliation: 1] Beijing Anzhen Hospital, Capital Medical University, Beijing, China [2] Key Laboratory of Remodeling-Related Cardiovascular Diseases, Capital Medical University, Ministry of Education, Beijing Institute of Heart Lung and Blood Vessel Diseases, Beijing collaborative innovative research center for cardiovascular diseases, Beijing, China.
authors.forename: J
authors.initials: J
authors.lastname: Du
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008099:Liver / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000556:secondary*; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009362:Neoplasm Metastasis / Q000473:pathology; D010587:Phagocytosis / Q000276:immunology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: C090509:Icam1 protein, mouse; D018799:Intercellular Adhesion Molecule-1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt