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

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

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.

Keywords: CD8(+) T cells; Kyn transporter; PD-1 upregulation; aryl hydrocarbon receptor; kynurenine; transcellular delivery; tumor-repopulating cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Cell Line, Tumor
  • Humans
  • Interferon-gamma / immunology
  • Kynurenine / pharmacology*
  • Mice
  • Programmed Cell Death 1 Receptor / drug effects*
  • Programmed Cell Death 1 Receptor / immunology
  • Programmed Cell Death 1 Receptor / metabolism
  • Receptors, Aryl Hydrocarbon / drug effects*
  • Signal Transduction / drug effects
  • Signal Transduction / immunology

Substances

  • PDCD1 protein, human
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Aryl Hydrocarbon
  • Kynurenine
  • Interferon-gamma