Role of TGF-β signaling in generation of CD39+CD73+ myeloid cells in tumors.
Role of TGF-β signaling in generation of CD39+CD73+ myeloid cells in tumors.
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DOI：
10.4049/jimmunol.1400578
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发表时间：
2014-09-15
期刊：
影响因子：
--
通讯作者：
Novitskiy SV
中科院分区：
文献类型：
--
作者：
Ryzhov SV;Pickup MW;Chytil A;Gorska AE;Zhang Q;Owens P;Feoktistov I;Moses HL;Novitskiy SV
越来越多的证据表明，由CD 39/CD 73酶对介导的ATP生成腺苷预先决定了骨髓细胞的免疫抑制和促血管生成特性。我们先前已经表明，髓样细胞中TGFβ II型受体基因（Tgfbr 2）表达的缺失与肿瘤生长减少相关，表明TGFβ信号传导的促肿瘤发生作用。在这项研究中，我们测试了TGFβ驱动髓源性抑制细胞（MDSC）分化为促肿瘤发生终末分化的髓样单核细胞（TDMMCs）的假设，其特征是高水平的细胞表面CD 39/CD 73表达。我们发现TDMMCs代表了肿瘤微环境中表达高水平CD 39和CD 73的主要细胞亚群。在从MMTV-PyMT/TGFRIIIKO小鼠分离的肿瘤中，与具有完整TGFβ信号传导的MMTV-PyMT/TGFRIIWT对照肿瘤相比，TGFβ蛋白水平的增加与CD 39 + CD 73 + TDMMC数量的进一步增加相关。利用遗传学和药理学方法，我们证明了TGFβ信号传导介导MDSC成熟为具有高水平细胞表面CD 39/CD 73表达和腺苷生成能力的TDMMCs。骨髓细胞中TGFβ信号传导的破坏导致表达CD 39和CD 73的TDMMC的积累减少，并伴随T淋巴细胞浸润增加、血管密度降低以及刘易斯肺癌和自发性乳腺癌的进展减缓。我们认为，TGFβ信号传导可以直接诱导CD 39 + CD 73 + TDMMC的产生，从而有助于这种多效性效应物在肿瘤微环境中的免疫抑制、促血管生成和肿瘤促进作用。
There is growing evidence that generation of adenosine from ATP, which is mediated by the CD39/CD73 enzyme pair, predetermines immunosuppressive and pro-angiogenic properties of myeloid cells. We have previously shown that the deletion of the TGFβ type II receptor gene (Tgfbr2) expression in myeloid cells is associated with decreased tumor growth suggesting pro-tumorigenic effect of TGFβ signaling. In this study, we tested the hypothesis that TGFβ drives differentiation of myeloid-derived suppressor cells (MDSCs) into pro-tumorigenic terminally differentiated myeloid mononuclear cells (TDMMCs) characterized by high levels of cell surface CD39/CD73 expression. We found that TDMMCs represent a major cell subpopulation expressing high levels of both CD39 and CD73 in the tumor microenvironment. In tumors isolated from MMTV-PyMT/TGFRIIKO mice, an increased level of TGFβ protein was associated with further increase in number of CD39+CD73+ TDMMCs compared to MMTV-PyMT/TGFRIIWT control tumors with intact TGFβ signaling. Using genetic and pharmacological approaches, we demonstrated that the TGFβ signaling mediates maturation of MDSCs into TDMMCs with high levels of cell surface CD39/CD73 expression and adenosine-generating capacity. Disruption of TGFβ signaling in myeloid cells resulted in decreased accumulation of TDMMCs, expressing CD39 and CD73, and was accompanied by increased infiltration of T lymphocytes, reduced density of blood vessels and diminished progression of both Lewis Lung carcinoma and spontaneous mammary carcinomas. We propose that TGFβ signaling can directly induce the generation of CD39+CD73+ TDMMCs, thus contributing to the immunosuppressive, pro-angiogenic, and tumor-promoting effects of this pleiotropic effector in the tumor microenvironment.
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