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.

中文翻译：

---

肿瘤繁殖细胞通过转移Kynurenine和AhR激活而诱导CD8 + T细胞中PD-1表达。

尽管免疫检查点抑制剂促进了临床成功，但肿瘤浸润性T细胞中PD-1上调的潜在机制仍是一个谜。在这里，我们显示肿瘤繁殖细胞（TRCs）通过跨细胞的犬尿氨酸（Kyn）-芳烃受体（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TRC产生的高水平Kyn释放，并被转移到相邻的CD8 ⁺T细胞通过转运蛋白SLC7A8和PAT4。Kyn诱导并激活AhR，从而上调PD-1表达。此Kyn-AhR途径在荷瘤小鼠和癌症患者中均得到证实，其阻断作用增强了抗肿瘤过继T细胞疗法的疗效。因此，我们发现了PD-1上调与潜在的肿瘤免疫治疗应用的机制。