Tumor-repopulating cells release Kyn, which activates AhR on T cells to promote PD-1 upregulation.

  • Major finding: Tumor-repopulating cells release Kyn, which activates AhR on T cells to promote PD-1 upregulation.

  • Mechanism: CD8+ T cells release IFNγ that stimulates Kyn release from tumor-repopulating cells.

  • Impact: The Kyn–AhR pathway may potentially be targeted to enhance the efficacy of adoptive T-cell therapy.

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Therapeutic targeting of PD-1 has yielded responses in patients with a variety of tumor types, but response rates remain low, indicating a need for new approaches to target PD-1. Further, the molecular mechanisms responsible for upregulating PD-1 in tumor-infiltrating cytotoxic CD8+ T lymphocytes (CTL) remain unknown. Liu, Liang, Dong, and colleagues investigated the interactions between CD8+ T cells and immunoevasive stem cell–like tumor-repopulating cells (TRC) to determine the effect on PD-1 expression and TRC immune evasion. IFNγ secreted by CTLs activated TRCs that in turn upregulated PD-1 on T cells. This upregulation of PD-1 resulted in reduced cytotoxic activity in CTLs. Mechanistically, IFNγ upregulated IDO1, an enzyme that catalyzes tryptophan to produce kynurenine (Kyn), in TRCs resulting in Kyn production. Kyn was then transported into CTLs, via the SLC7A8 and PAT4 transporters, where it activated the aryl hydrocarbon receptor (AhR), a cytoplasmic transcription factor that is then translocated to the nucleus to upregulate PD-1 in CTLs. This Kyn–AhR-mediated upregulation of PD-1 was independent of T-cell receptor (TCR) signaling, but Kyn-induced PD-1 upregulation could be further enhanced by TCR signaling. In vivo, Kyn injection promoted PD-1 upregulation, which could be abrogated by Ahr deletion. Further, Kyn promoted upregulation of PD-1 In the tumor microenvironment of tumor-bearing mice. In a mouse melanoma model, adoptive T-cell therapy reduced tumor growth, and the efficacy was enhanced by an anti–PD-1 antibody. Inhibiting AhR had a similar effect to blocking PD-1, suppressing tumor growth and enhancing adoptive T-cell therapy. Moreover, Kyn–AhR promoted PD-1 upregulation in CD8+ T cells from patients with cancer. Altogether, these findings identify a Kyn–AhR dependent mechanism by which PD-1 can be upregulated on CTLs to promote TRC immune escape and suggest the potential for therapeutic targeting of the Kyn–AhR pathway.

Liu Y, Liang X, Dong W, Fang Y, Lv J, Zhang T, et al. Tumor-repopulating cells induce PD-1 expression in CD8+ T cells by transferring kynurenine and AhR activation. Cancer Cell 2018;33:480–94.e7.

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©2018 American Association for Cancer Research.
2018
American Association for Cancer Research.