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Cancer Cell. 2018 Mar 12;33(3):480-494.e7. doi: 10.1016/j.ccell.2018.02.005.

Tumor-Repopulating Cells Induce PD-1 Expression in CD8+ T Cells by Transferring Kynurenine and AhR Activation.

Author information

1
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.
2
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.
3
National Cancer Center/Cancer Hospital, CAMS, Beijing 100005, China.
4
Department of Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China.
5
State Key Laboratory of Trauma, Burns and Combined Injury, Department 1, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China.
6
Department of Gastroenterology, Peking Union Medical College Hospital, CAMS, Beijing 100005, China.
7
Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, CAMS, Beijing 100005, China.
8
Center of Systems Medicine, Institute of Basic Medical Sciences, CAMS & Suzhou Institute of Systems Medicine, Suzhou 215123, China.
9
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 Biochemistry & Molecular Biology, Tongji Medical College, Huazhong University of Science & Technology, Wuhan 430030, China. Electronic address: tjhuangbo@hotmail.com.

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.

KEYWORDS:

CD8(+) T cells; Kyn transporter; PD-1 upregulation; aryl hydrocarbon receptor; kynurenine; transcellular delivery; tumor-repopulating cells

PMID:
29533786
DOI:
10.1016/j.ccell.2018.02.005
[Indexed for MEDLINE]
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