Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets
Tumor-Derived Mesenchymal Stem Cells Use Distinct Mechanisms to Block the Activity of Natural Killer Cell Subsets
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DOI：
10.1016/j.celrep.2017.08.089
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发表时间：
2017-09-19
期刊：
影响因子：
8.8
通讯作者：
Stamenkovic, Ivan
中科院分区：
文献类型：
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作者：
Galland, Sabine;Vuille, Joanna;Stamenkovic, Ivan
间充质干细胞（MSC）显示出多效性功能，包括分泌具有与癌症进展有关的免疫抑制活性的可溶性因子。我们比较了来自鳞状细胞肺癌（SCC）患者的成对瘤内（T）和邻近非肿瘤组织（N）来源的MSC对自然杀伤（NK）细胞的免疫调节作用。我们观察到T-MSCs比N-MSCs具有更强的免疫抑制作用，并且影响NK功能和表型，如通过CD 56表达所定义的。T-MSC使NK细胞向CD 56（dim）表型转移，并差异调节CD 56（亮/暗）亚群功能。尽管MSC影响CD 56（暗淡）亚群中的脱粒和活化受体表达，但它们主要抑制CD 56（明亮）亚群中的干扰素-γ产生。药理学抑制前列腺素E2（PGE 2）的合成，并在一些MSC，白细胞介素-6（IL-6）的活性恢复NK功能，而NK细胞刺激PGE 2单独模仿T-MSC介导的免疫抑制。我们的观察提供了深入了解如何基质反应，癌症抑制NK细胞活性在人肺SCC。
Mesenchymal stem cells (MSCs) display pleiotropic functions, which include secretion of soluble factors with immunosuppressive activity implicated in cancer progression. We compared the immunomodulatory effects on natural killer (NK) cells of paired intratumor (T)- and adjacent non-tumor tissue (N)-derived MSCs from patients with squamous cell lung carcinoma (SCC). We observed that T-MSCs were more strongly immunosuppressive than N-MSCs and affected both NK function and phenotype, as defined by CD56 expression. T-MSCs shifted NK cells toward the CD56(dim) phenotype and differentially modulated CD56(bright/dim) subset functions. Whereas MSCs affected both degranulation and activating receptor expression in the CD56(dim) subset, they primarily inhibited interferon-gamma production in the CD56(bright) subset. Pharmacological inhibition of prostaglandin E2 (PGE2) synthesis and, in some MSCs, interleukin-6 (IL-6) activity restored NK function, whereas NK cell stimulation by PGE2 alone mimicked T-MSC-mediated immunosuppression. Our observations provide insight into how stromal responses to cancer dampen NK cell activity in human lung SCC.