| Literature DB >> 29533786 |
Yuying Liu1, Xiaoyu Liang2, Wenqian Dong2, Yi Fang3, Jiadi Lv2, Tianzhen Zhang2, Roland Fiskesund2, Jing Xie2, Jinyan Liu2, Xiaonan Yin2, Xun Jin2, Degao Chen2, Ke Tang4, Jingwei Ma4, Huafeng Zhang4, Jing Yu5, Jun Yan5, Huaping Liang5, Siqi Mo2, Feiran Cheng2, Yabo Zhou2, Haizeng Zhang3, Jing Wang3, Jingnan Li6, Yang Chen6, Bing Cui7, Zhuo-Wei Hu7, Xuetao Cao2, F Xiao-Feng Qin8, Bo Huang9.
Abstract
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.Entities:
Keywords: CD8(+) T cells; Kyn transporter; PD-1 upregulation; aryl hydrocarbon receptor; kynurenine; transcellular delivery; tumor-repopulating cells
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Year: 2018 PMID： 29533786 DOI： 10.1016/j.ccell.2018.02.005
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743