Tumor-repopulating cells induce PD-1 expression in CD8(+) T cells by transferring kynurenine and AhR activation
Open accessAbstract
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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The Kyn-AhR interaction upregulates PD-1 expression by CD8+ T cells via transcellular signaling in the tumor microenvironment.
“In addition, the Kyn-AhR interaction has been shown to upregulate PD-1 expression by CD8+ T cells via transcellular signaling mechanism in the tumor microenvironment (42).”
From Reimagining IDO Pathway Inhibition in Cancer Immunotherapy via Downstream Focus on the Tryptophan–Kynurenine–Aryl Hydrocarbon Axis (2019) · cites this paper as [42]
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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
- ORCID
- 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
- bronze
- doi.org
- Licence
- 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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