TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer.
TGFβ1-Mediated SMAD3 Enhances PD-1 Expression on Antigen-Specific T Cells in Cancer.
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DOI：
10.1158/2159-8290.cd-15-1347
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发表时间：
2016-12
期刊：
影响因子：
28.2
通讯作者：
Cox AL
中科院分区：
文献类型：
--
作者：
Park BV;Freeman ZT;Ghasemzadeh A;Chattergoon MA;Rutebemberwa A;Steigner J;Winter ME;Huynh TV;Sebald SM;Lee SJ;Pan F;Pardoll DM;Cox AL
程序性死亡-1 （PD-1）是一种共抑制受体，在癌症中下调肿瘤浸润淋巴细胞（TIL）的活性，在慢性感染中下调病毒特异性T细胞的活性。在TIL上驱动PD-1高表达的分子机制尚未得到充分的研究。我们证明了转化生长因子-β1 （TGF-β1）在体外T细胞和体内TIL中通过smad3依赖和smad2独立的转录激活直接增强抗原诱导的PD-1表达。在CD8+ TIL中发现的PD-1hi亚群在smad3缺陷的肿瘤特异性CD8+ TIL中缺失，导致TIL细胞因子产生增强，淋巴结引流和抗肿瘤活性增强。除了先前已知的TGF-β1对T细胞功能的影响外，我们的研究结果表明TGF-β1通过在TME中上调PD-1介导T细胞抑制。他们强调了效应物TIL和TGF-β产生细胞之间的双向串扰，该串扰上调了PD-1信号通路的多个组分，从而抑制抗肿瘤免疫。
Programmed Death-1 (PD-1) is a co-inhibitory receptor that down-regulates the activity of tumor-infiltrating lymphocytes (TIL) in cancer and of virus-specific T cells in chronic infection. The molecular mechanisms driving high PD-1 expression on TIL have not been fully investigated. We demonstrate that transforming growth factor-β1 (TGF-β1) directly enhances antigen-induced PD-1 expression through Smad3-dependent, Smad2-independent transcriptional activation in T cells in vitro and in TIL in vivo. The PD-1hi subset seen in CD8+ TIL is absent in Smad3-deficient tumor-specific CD8+ TIL, resulting in enhanced cytokine production by TIL and in draining lymph nodes and of anti-tumor activity. In addition to TGF-β1’s previously known effects on T cell function, our findings suggest that TGF-β1 mediates T cell suppression via PD-1 upregulation in the TME. They highlight bidirectional crosstalk between effector TIL and TGF-β-producing cells that upregulates multiple components of the PD-1 signaling pathway to inhibit anti-tumor immunity.