Cited by 535Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

Tumor-repopulating cells induce PD-1 expression in CD8(+) T cells by transferring kynurenine and AhR activation

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Liu, Yuying, Liang, Xiaoyu, Dong, Wenqian, Fang, Yi, Lv, Jiadi, Zhang, Tianzhen, Fiskesund, Roland, Xie, Jing +22 more·2018·Cancer Cell

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.

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Crossref · 10.1016/j.ccell.2018.02.005

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Authors
Liu, Y., Liang, X., Dong, W., Fang, Y., Lv, J., Zhang, T., Fiskesund, R., Xie, J., Liu, J., Yin, X., Jin, X., Chen, D., Tang, K., Ma, J., Zhang, H., Yu, J., Yan, J., Liang, H., Mo, S., Cheng, F., Zhou, Y., Zhang, H., Wang, J., Li, J., Chen, Y., Cui, B., Hu, Z.-W., Cao, X., Xiao-Feng Qin, F., & Huang, B.
Affiliations
  • Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
  • Huazhong University of Science and Technology (CN)
  • Army Medical University (CN)
  • Peking Union Medical College Hospital (CN)
Corresponding author
Huang, Bo
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2018-03
Volume
33
Issue
3
Pages
480-494.e7
ISSN
1535-6108 (ISSN-L)
OpenAlex
W2790897054
Cited by
535
References
38
Citations by year
2026: 67 · 2025: 75 · 2024: 73 · 2023: 78 · 2022: 70 · 2021: 89 · 2020: 47 · 2019: 24 · 2018: 12
FWCI
16.63
Type
journal article
Language
en
Open access
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (81788101, 81661128007, 81530080, 81773062, 81773058)
  • CAMS (2016-I2M-1-007)
Topics
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords
tumor-repopulating cells, CD8+ T cells, kynurenine, aryl hydrocarbon receptor, SLC7A8, interferon-gamma, cancer immunotherapy, adoptive T cell therapy, immune checkpoint
MeSH terms
Animals, Humans, Interferon-gamma, Kynurenine, Signal Transduction, Receptors, Aryl Hydrocarbon, CD8-Positive T-Lymphocytes, Cell Line, Tumor, Mice, Programmed Cell Death 1 Receptor

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