Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease
Reduction of myeloid-derived suppressor cells and induction of M1 macrophages facilitate the rejection of established metastatic disease
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DOI：
10.4049/jimmunol.174.2.636
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发表时间：
2005-01-15
影响因子：
4.4
通讯作者：
Ostrand-Rosenberg, S
中科院分区：
文献类型：
--
作者：
Sinha, P;Clements, VK;Ostrand-Rosenberg, S
超过60%的STAT 6（-/-）小鼠免疫排斥自发性转移性乳腺癌，并且如果其原发性肿瘤被去除，则无限期地存活，而95%的具有STAT 6活性的BALB/c小鼠死于转移性疾病。原发性肿瘤的BALB/c和STAT 6缺陷小鼠具有升高水平的Gr 1（+）CD 11b（+）骨髓抑制细胞（MSC），其抑制T细胞活化。在去除原发性肿瘤后，STAT 6缺陷型小鼠的MSC水平恢复到基线水平，但在BALB/c小鼠中仍然升高。这种减少是IFN-γ依赖性的，转移性疾病的减少也是如此。无论是BALB/c，也没有STAT 6缺陷的MSC产生诱导型NO合酶，但是，都产生过氧化物酶和活性氧。STAT 6缺陷型小鼠产生M1巨噬细胞，其含有高水平的NO并且是杀肿瘤的，而BALB/c小鼠产生M2巨噬细胞，其产生谷胱甘肽酶并且不是杀肿瘤的。STAT 6缺陷小鼠的免疫需要激活NO产生的MI巨噬细胞，这些巨噬细胞是杀肿瘤的，手术切除原发性肿瘤后MSC水平降低至基线，以及激活肿瘤特异性T细胞。这些机制发生在STAT 6（-/-）小鼠中，因为STAT 6缺陷阻止了通过2型IL-4 R α的信号传导，从而阻断了IL-4酶的产生并促进了NO的合成。
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 MI 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.