Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China; Clinical Immunology Center, CAMS, Beijing 100005, China.
Department of Immunology & National Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences (CAMS) & Peking Union Medical College, Beijing 100005, China.
Cancer Cell. 2018 Mar 12;33(3):480-494.e7. doi: 10.1016/j.ccell.2018.02.005.
Despite the clinical successes fostered by immune checkpoint inhibitors, mechanisms underlying PD-1 upregulation in tumor-infiltrating T cells remain an enigma. Here, we show that tumor-repopulating cells (TRCs) drive PD-1 upregulation in CD8 T cells through a transcellular kynurenine (Kyn)-aryl hydrocarbon receptor (AhR) pathway. Interferon-γ produced by CD8 T cells stimulates release of high levels of Kyn produced by TRCs, which is transferred into adjacent CD8 T cells via the transporters SLC7A8 and PAT4. Kyn induces and activates AhR and thereby upregulates PD-1 expression. This Kyn-AhR pathway is confirmed in both tumor-bearing mice and cancer patients and its blockade enhances antitumor adoptive T cell therapy efficacy. Thus, we uncovered a mechanism of PD-1 upregulation with potential tumor immunotherapeutic applications.
尽管免疫检查点抑制剂带来了临床成功，但肿瘤浸润 T 细胞中 PD-1 上调的机制仍然是一个谜。在这里，我们表明，肿瘤再殖细胞（TRCs）通过跨细胞色氨酸（Kyn）-芳香烃受体（AhR）途径驱动 CD8 T 细胞中 PD-1 的上调。CD8 T 细胞产生的干扰素-γ刺激 TRCs 释放高水平的 Kyn，这些 Kyn 通过转运体 SLC7A8 和 PAT4 转移到相邻的 CD8 T 细胞中。Kyn 诱导并激活 AhR，从而上调 PD-1 的表达。在荷瘤小鼠和癌症患者中均证实了这种 Kyn-AhR 途径，其阻断增强了抗肿瘤过继 T 细胞治疗的疗效。因此，我们揭示了一种具有潜在肿瘤免疫治疗应用的 PD-1 上调机制。
