Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis.
CD1-deficient mice reject established, disseminated 4T1 metastatic mammary cancer and survive indefinitely if their primary mammary tumors are surgically removed. This highly effective immune surveillance is due to three interacting mechanisms: (a) the generation of inducible nitric oxide synthase (iNOS)-producing M1 macrophages that are tumoricidal for 4T1 tumor cells; (b) a rapid decrease in myeloid-derived Gr1(+)CD11b(+) suppressor cells that are elevated and down-regulate the CD3zeta chain when primary tumor is present and that suppress T cells by producing arginase; and (c) production of activated lymphocytes. Macrophages from wild-type BALB/c mice are polarized by interleukin-13 (IL-13) towards a tumor-promoting M2 phenotype, thereby inhibiting the generation of tumoricidal M1 macrophages. In contrast, CD1(-/-) mice, which are deficient for IL-13 because they lack IL-13-producting NKT cells, generate M1 macrophages that are cytotoxic for 4T1 via the production of nitric oxide. Although tumoricidal macrophages are a necessary component of immune surveillance in CD1(-/-) mice, they alone are not sufficient for tumor resistance because IL-4Ralpha(-/-) mice have M1 macrophages and retain high levels of myeloid suppressor cells after surgery; in addition, they are susceptible to 4T1 metastatic disease. These results show that effective immune surveillance against established metastatic disease is negatively regulated by IL-13 and requires the induction of tumoricidal M1 macrophages and lymphocytes combined with a reduction in tumor-induced myeloid suppressor cells.
Sinha
Pratima
P
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, 21250, USA.
Clements
Virginia K
VK
Ostrand-Rosenberg
Suzanne
S
D000818:Animals; D018949:Antigens, CD1 / Q000235:genetics / Q000502:physiology; D001119:Arginase / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D017252:CD3 Complex / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics*; D007157:Immunologic Surveillance; D018793:Interleukin-13 / Q000235:genetics / Q000502:physiology*; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D008213:Lymphocyte Activation; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000601:surgery; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D050800:STAT6 Transcription Factor / Q000235:genetics / Q000502:physiology; D013601:T-Lymphocytes / Q000201:enzymology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology
D018949:Antigens, CD1; D039481:CD11b Antigen; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; D018793:Interleukin-13; D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase