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

Liu Y1, Liang X2, Dong W2, Fang Y3, Lv J2, Zhang T2, Fiskesund R2, Xie J2, Liu J2, Yin X2, Jin X2, Chen D2, Tang K4, Ma J4, Zhang H4, Yu J5, Yan J5, Liang H5, Mo S2, Cheng F2, Zhou Y2, Zhang H3, Wang J3, Li J6, Chen Y6, Cui B7, Hu ZW7, Cao X2, Xiao-Feng Qin F8, Huang B9.

Cancer Cell. 2018 Mar 12;33(3):480-494.e7. doi: 10.1016/j.ccell.2018.02.005.
PMID: 29533786

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.