Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease.
More than 60% of STAT6(-/-) mice immunologically reject spontaneous metastatic mammary carcinoma and survive indefinitely if their primary tumors are removed, whereas 95% of STAT6-competent BALB/c mice succumb to metastatic disease. BALB/c and STAT6-deficient mice with primary tumors have elevated levels of Gr1(+)CD11b(+) myeloid suppressor cells (MSCs), which inhibit T cell activation. After removal of primary tumor, MSC levels revert to baseline in STAT6-deficient mice, but remain elevated in BALB/c mice. The decrease is IFN-gamma dependent, as is the reduction in metastatic disease. Neither BALB/c nor STAT6-deficient MSCs produce inducible NO synthase; however, both produce arginase and reactive oxygen species. STAT6-deficient mice produce M1 macrophages, which contain high levels of NO and are tumoricidal, whereas BALB/c mice produce M2 macrophages, which make arginase and are not tumoricidal. Immunity in STAT6-deficient mice requires the activation of NO-producing M1 macrophages that are tumoricidal, the reduction in MSC levels to baseline after surgical removal of primary tumor, and the activation of tumor-specific T cells. These mechanisms occur in STAT6(-/-) mice because STAT6 deficiency prevents signaling through the type 2 IL-4Ralpha, thereby blocking the production of arginase and promoting the synthesis of NO.
Sinha
Pratima
P
Department of Biological Sciences, University of Maryland Baltimore County, Baltimore, MD 21250, USA.
Clements
Virginia K
VK
Ostrand-Rosenberg
Suzanne
S
D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D002460:Cell Line; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000096:biosynthesis; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000517:prevention & control* / Q000556:secondary*; D008262:Macrophage Activation / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology*; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000276:immunology / Q000601:surgery; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D010641:Phenotype; D050800:STAT6 Transcription Factor; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology*; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics
D050800:STAT6 Transcription Factor; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D001119:Arginase