Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease

P Sinha, VK Clements… - The Journal of …, 2005 - journals.aai.org
The Journal of Immunology, 2005journals.aai.org
Abstract 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 …
Abstract
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-γ 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-4Rα, thereby blocking the production of arginase and promoting the synthesis of NO.
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