Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis
Interleukin-13-regulated M2 macrophages in combination with myeloid suppressor cells block immune surveillance against metastasis
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DOI：
10.1158/0008-5472.can-05-0045
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发表时间：
2005-12-15
期刊：
影响因子：
11.2
通讯作者：
Ostrand-Rosenberg, S
中科院分区：
文献类型：
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作者：
Sinha, P;Clements, VK;Ostrand-Rosenberg, S
CM缺陷小鼠排斥已建立的、播散性4 T1转移性乳腺癌，如果手术切除其原发性乳腺肿瘤，则无限期存活。这种高度有效的免疫监视是由于三种相互作用的机制：（a）产生诱导型一氧化氮合酶（iNOS）的M1巨噬细胞，其对4 T1肿瘤细胞具有杀瘤作用;（B）骨髓来源的Gr 1（+）CD 11 B（+）抑制细胞的快速减少，当原发性肿瘤存在时，所述抑制细胞升高并下调CD 3 ζ链，并且通过产生抗肿瘤酶抑制T细胞;和（c）产生活化的淋巴细胞。来自野生型BALB/c小鼠的巨噬细胞通过白细胞介素-13（IL-13）极化为促肿瘤M2表型，从而抑制杀肿瘤M1巨噬细胞的产生。相反，由于缺乏产生IL-13的NKT细胞而缺乏IL-13的CD 1（-/-）小鼠通过产生一氧化氮产生对4 T1具有细胞毒性的M1巨噬细胞。尽管杀肿瘤巨噬细胞是CD 1（-/-）小鼠免疫监视的必要组成部分，但它们本身不足以产生肿瘤抗性，因为IL-4 R α（-/-）小鼠具有M1巨噬细胞，并在手术后保留高水平的髓系抑制细胞;此外，它们对4 T1转移性疾病易感。这些结果表明，对已建立的转移性疾病的有效免疫监视是由IL-13负调控的，需要诱导杀肿瘤的M1巨噬细胞和淋巴细胞，并减少肿瘤诱导的骨髓抑制细胞。
CM-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 Grl(+)CD11b(+) suppressor cells that are elevated and down-regulate the CD3 zeta chain when primary tumor is present and that suppress T cells by producing arginase; and (c) production of activated lymphocytes. Macrophages from wildtype 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-4R alpha(-/-) 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.