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肿瘤再生细胞通过Kyn-AhR信号通路上调T细胞中PD-1分子的表达

  • 发布时间:2021-09-07
  • 浏 览:3151次

研究亮点

lCD8+ T细胞产生的IFN-γ刺激肿瘤再生细胞释放犬尿氨酸(Kyn);

lKyn被转移到CD8+ T细胞中;

lKyn激活芳香烃受体(AhR)后上调CD8+ T细胞PD-1的表达;

lTCR信号通路通过上调Kyn转运蛋白促进Kyn-AhR信号通路激活.

 

研究摘要

肿瘤再生细胞(Tumor-Repopulating CellTRCs)也被称作肿瘤干细胞是肿瘤发生的种子细胞也是肿瘤耐药的根本原因.此外尽管以PD-1为靶点的免疫检查点抑制剂于肿瘤临床治疗中取得了较大的成功但肿瘤浸润性T细胞中PD-1的上调机制尚不清楚.

本研究显示通过跨细胞信号通路(Kyn-AhRTRCs可促进CD8+ T细胞中PD-1的表达.由CD8+ T细胞产生的IFN-γ刺激TRCs产生大量Kyn并释放(图1)通过转运蛋白SLC7A8PAT4转移到邻近的CD8+ T细胞中.CD8+ T细胞中的Kyn可诱导激活AhR从而上调PD-1的表达(图2).该Kyn-AhR途径于荷瘤小鼠和癌症患者中均得到证实阻断该通路可增强过继性T细胞疗法的抗肿瘤功效.该研究发现的PD-1上调机制将为肿瘤免疫治疗策略提供1种新的思路.

 

1 CD8+ T细胞产生的IFN-γ刺激TRCs产生大量Kyn

 

 

2 Kyn可诱导激活AhR上调PD-1的表达

 

参考文献:Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation. 2018,Cancer Cell 33, 480–494. https://doi.org/10.1016/j.ccell.2018.02.005

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