Alternatively activated macrophage possess antitumor cytotoxicity that is induced by IL-4 and mediated by arginase-1.
Earlier studies have shown that the adoptive transfer of Th2-polarized CD4 T cells can clear established tumors from mice in an antigen-specific manner. Although eosinophils were implicated in this process, the exact mechanism of tumor clearance and which immune effector cells were involved, remain to be defined. Consequently, experiments were undertaken to elucidate the mechanism of Th2-mediated destruction of B16-F1 melanoma cells by examining the in vitro antitumor activity of leukocytes within a type-2 inflammatory infiltrate. The experimental data show that activation of alternatively activated macrophages (aaMacs) within type-2 infiltrates by IL-4 or IL-13 can inhibit B16-F1 melanoma cell proliferation through a mechanism that is dependent on arginase-1 depletion of L-arginine within the tumor cell microenvironment. Interestingly, whilst at higher E:T ratios aaMac exhibited antitumor activity, at lower E:T ratios aaMacs were observed to enhance rather than inhibit B16-F1 melanoma cell growth. This highlights the fine balance between stimulating the antitumorigenic and protumorigenic properties of aaMacs in tumor immunotherapy protocols.
Ellyard
Julia I
JI
Cancer and Vascular Biology Group, Division of Immunology and Genetics, John Curtin School of Medical Research, Australian National University daggerCancer Immunotherapy Group, Biomedical Sciences, Faculty of Applied Science, University of Canberra, Canberra, Australia.
Quah
Ben J C
BJ
Simson
Ljubov
L
Parish
Christopher R
CR
D000818:Animals; D001119:Arginase / Q000378:metabolism*; D049109:Cell Proliferation; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D019672:Genes, T-Cell Receptor / Q000235:genetics; D016219:Immunotherapy, Adoptive; D015847:Interleukin-4 / Q000276:immunology* / Q000378:metabolism; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D015847:Interleukin-4; D010047:Ovalbumin; C544448:Arg1 protein, mouse; D001119:Arginase