Combined GM-CSF treatment and M-CSF inhibition of tumor-associated macrophages induces dendritic cell-like signaling in vitro
Combined GM-CSF treatment and M-CSF inhibition of tumor-associated macrophages induces dendritic cell-like signaling in vitro
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DOI：
10.3892/ijo.2011.960
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发表时间：
2011-05-01
影响因子：
5.2
通讯作者：
Takami, Tsuyoshi
中科院分区：
文献类型：
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作者：
Kitoh, Yusuke;Saio, Masanao;Takami, Tsuyoshi
巨噬细胞表现出可塑性，并且肿瘤相关巨噬细胞（TAM）可以在肿瘤微环境中充当免疫抑制细胞。因此，在这项研究中，我们的目的是在体外重新编程TAM与细胞因子信号的改变。单独的粒细胞巨噬细胞集落刺激因子（GM-CSF）处理不会导致TAM在体外表达M1（包括IL-1 β、TNF α和CXCL-10）或M2（包括CD 36、CD 206和CCL 17）分子的变化，尽管它们采用圆形形态并且与培养皿的粘附性较低。当针对巨噬细胞集落刺激因子（M-CSF）受体（M-CSFR）的siRNA联合GM-CSF处理抑制M-CSF信号时，TAM的信号转导途径改变，并且通常由树突状细胞表达的STAT 1、STAT 5和STAT 6的表达增加。然而，相同的处理并没有改变M1/M2标记分子的TAM表达模式。对于NF-κ B途径，GM-CSF和M-CSFR siRNA联合处理显著诱导TAM通常不表达的p65的表达，而TAM的p50和p105表达不受处理的影响。这些发现表明，我们的模型不能重定向TAM的单核细胞衍生的树突状细胞样表型的基础上分析M1/M2标记物的表达，但它能够修改细胞信号转导通路向树突状细胞样的模式。因此，目前的数据表明，TAM表现出对树突状细胞样信号转导模式的可塑性，并且肿瘤微环境的改变有可能逆转TAM的免疫抑制特性。
Macrophages demonstrate plasticity, and tumor-associated macrophages (TAM) can function as immunosuppressive cells in the tumor microenvironment. Therefore, in this study, we aimed to reprogram TAM in vitro with cytokine signal alteration. Granulocyte macrophage colony stimulating factor (GM-CSF) treatment alone did not lead to changes in the expression of M1 (including IL-1 beta, TNF alpha, and CXCL-10) or M2 (including CD36, CD206 and CCL17) molecules by TAM in vitro, although they adopted a round morphology and were less adhesive to the culture dish. When macrophage colony stimulating factor (M-CSF) signals were suppressed by siRNA against the M-CSF receptor (M-CSFR) in conjunction with GM-CSF treatment, the signal transduction pathway of TAM was altered, and the expression of STAT1, STAT5 and STAT6, which are usually expressed by dendritic cells, was increased. However, the same treatment did not alter the TAM expression pattern of M1/M2 marker molecules. With respect to the NF-kappa B pathway, GM-CSF and M-CSFR siRNA combination treatment significantly induced the expression of p65, which is usually not expressed by TAM, while p50 and p105 expression by TAM was not affected by the treatment. These findings indicate that our model could not redirect TAM to a monocyte-derived dendritic cell-like phenotype based on the analysis of M1/M2 marker expression, but it was able to modify cell signaling pathways toward a dendritic cell-like pattern. Therefore, the present data suggest that TAM demonstrate plasticity toward dendritic cell-like signal transduction patterns, and that the alteration of the tumor microenvironment has the potential to reverse the immunosuppressive properties of TAM.