Journal
CANCER CELL
Volume 33, Issue 3, Pages 480-+Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2018.02.005
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Funding
- National Natural Science Foundation of China [81788101, 81661128007, 81530080, 81773062, 81773058]
- CAMS Initiative for Innovative Medicine [2016-I2M-1-007]
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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-g 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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