title: Control of tumor-associated macrophage alternative activation by macrophage migration inhibitory factor.
abstract: Tumor stromal alternatively activated macrophages are important determinants of antitumor T lymphocyte responses, intratumoral neovascularization, and metastatic dissemination. Our recent efforts to investigate the mechanism of macrophage migration inhibitory factor (MIF) in antagonizing antimelanoma immune responses reveal that macrophage-derived MIF participates in macrophage alternative activation in melanoma-bearing mice. Both peripheral and tumor-associated macrophages (TAMs) isolated from melanoma bearing MIF-deficient mice display elevated proinflammatory cytokine expression and reduced anti-inflammatory, immunosuppressive, and proangiogenic gene products compared with macrophages from tumor-bearing MIF wild-type mice. Moreover, TAMs and myeloid-derived suppressor cells from MIF-deficient mice exhibit reduced T lymphocyte immunosuppressive activities compared with those from their wild-type littermates. Corresponding with reduced tumor immunosuppression and neo-angiogenic potential by TAMs, MIF deficiency confers protection against transplantable s.c. melanoma outgrowth and melanoma lung metastatic colonization. Finally, we report for the first time, to our knowledge, that our previously discovered MIF small molecule antagonist, 4-iodo-6-phenylpyrimidine, recapitulates MIF deficiency in vitro and in vivo, and attenuates tumor-polarized macrophage alternative activation, immunosuppression, neoangiogenesis, and melanoma tumor outgrowth. These studies describe an important functional contribution by MIF to TAM alternative activation and provide justification for immunotherapeutic targeting of MIF in melanoma patients.
authors: Molecular Targets Group, J.G. Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.
authors: Kavitha
authors: K
authors: Yaddanapudi
authors: Kalyani
authors: K
authors: Putty
authors: Beatriz E
authors: BE
authors: Rendon
authors: Gwyneth J
authors: GJ
authors: Lamont
authors: Jonathan D
authors: JD
authors: Faughn
authors: Abhay
authors: A
authors: Satoskar
authors: Amanda
authors: A
authors: Lasnik
authors: John W
authors: JW
authors: Eaton
authors: Robert A
authors: RA
authors: Mitchell
mesh_terms: D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D008175:Lung Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008263:Macrophage Migration-Inhibitory Factors / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic
chemical_list: D008263:Macrophage Migration-Inhibitory Factors
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