Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling.
Myeloid-Derived Suppressor Cells Endow Stem-like Qualities to Breast Cancer Cells through IL6/STAT3 and NO/NOTCH Cross-talk Signaling.
复制标题
通过IL6/STAT3和NO/Notch交叉交叉信号传导，髓样衍生的抑制细胞赋予乳腺癌细胞类似茎状的质量。
DOI：
10.1158/0008-5472.can-15-2528
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发表时间：
2016-06-01
期刊：
影响因子：
11.2
通讯作者：
Kryczek I
中科院分区：
文献类型：
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作者：
Peng D;Tanikawa T;Li W;Zhao L;Vatan L;Szeliga W;Wan S;Wei S;Wang Y;Liu Y;Staroslawska E;Szubstarski F;Rolinski J;Grywalska E;Stanisławek A;Polkowski W;Kurylcio A;Kleer C;Chang AE;Wicha M;Sabel M;Zou W;Kryczek I
骨髓源性抑制细胞（MDSC）有助于癌症的免疫抑制，但它们驱动转移进展的机制尚未完全了解。在这项研究中，我们展示了MDSC如何向乳腺癌细胞传递干细胞样品质，协调帮助实现免疫抑制和逃逸。我们发现MDSC通过增强乳腺癌细胞干细胞样特性以及抑制T细胞活化来促进肿瘤形成。机制研究表明，这些作用依赖于癌细胞中STAT 3和NOTCH通路之间的串扰，MDSC诱导STAT 3的IL-6依赖性磷酸化并通过一氧化氮（NO）激活NOTCH，导致STAT 3激活延长。在乳腺癌的临床标本中，MDSC的存在与癌症干细胞样细胞（CSC）的存在相关，并独立预测不良生存结局。总的来说，我们的工作揭示了一种免疫相关的机制，这种机制可以赋予癌细胞干细胞特性并影响患者的预后。我们认为，靶向MDSC和CSC之间的STAT 3-NOTCH串扰可以提供一个独特的位点，以改善癌症治疗，通过协调靶向一个耦合机制，使癌症干细胞和免疫逃逸。
Myeloid-derived suppressor cells (MDSC) contribute to immune suppression in cancer, but the mechanisms through which they drive metastatic progression are not fully understood. In this study, we show how MDSC convey stem-like qualities to breast cancer cells that coordinately help enable immune suppression and escape. We found that MDSC promoted tumor formation by enhancing breast cancer cell stem-like properties as well as by suppressing T cell activation. Mechanistic investigations indicated that these effects relied upon crosstalk between the STAT3 and NOTCH pathways in cancer cells, with MDSC inducing IL-6-dependent phosphorylation of STAT3 and activating NOTCH through nitric oxide (NO), leading to prolonged STAT3 activation. In clinical specimens of breast cancer, the presence of MDSC correlated with the presence of cancer stem-like cells (CSC) and independently predicted poor survival outcomes. Collectively, our work revealed an immune-associated mechanism that extrinsically confers cancer cell stemness properties and affects patient outcome. We suggest that targeting STAT3-NOTCH crosstalk between MDSC and CSC could offer a unique locus to improve cancer treatment, by coordinately targeting a coupled mechanism that enables cancer stemness and immune escape.