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PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma

Authors
  • Beldi-Ferchiou, Asma
  • Lambert, Marion
  • Dogniaux, Stéphanie
  • Vély, Frédéric
  • Vivier, Eric
  • Olive, Daniel
  • Dupuy, Stéphanie
  • Levasseur, Frank
  • Zucman, David
  • Lebbé, Céleste
  • Sène, Damien
  • Claire Hivroz
  • Sophie Caillat-Zucman
Type
Published Article
Journal
Oncotarget
Publisher
"Impact Journals, LLC "
Publication Date
Sep 01, 2016
Volume
7
Issue
45
Pages
72961–72977
Identifiers
DOI: 10.18632/oncotarget.12150
PMID: 27662664
PMCID: PMC5341956
Source
USPC - SET - SVS
License
Green

Abstract

Programmed Death-1 (PD-1), an inhibitory receptor expressed by activated lymphocytes, is involved in regulating T- and B-cell responses. PD-1 and its ligands are exploited by a variety of cancers to facilitate tumor escape through PD-1-mediated functional exhaustion of effector T cells. Here, we report that PD-1 is upregulated on Natural Killer (NK) cells from patients with Kaposi sarcoma (KS). PD-1 was expressed in a sub-population of activated, mature CD56dimCD16pos NK cells with otherwise normal expression of NK surface receptors. PD-1pos NK cells from KS patients were hyporesponsive ex vivo following direct triggering of NKp30, NKp46 or CD16 activating receptors, or short stimulation with NK cell targets. PD-1pos NK cells failed to degranulate and release IFNγ, but exogenous IL-2 or IL-15 restored this defect. That PD-1 contributed to NK cell functional impairment and was not simply a marker of dysfunctional NK cells was confirmed in PD-1-transduced NKL cells. In vitro, PD-1 was induced at the surface of healthy control NK cells upon prolonged contact with cells expressing activating ligands, i.e. a condition mimicking persistent stimulation by tumor cells. Thus, PD-1 appears to plays a critical role in mediating NK cell exhaustion. The existence of this negative checkpoint fine-tuning NK activation highlights the possibility that manipulation of the PD-1 pathway may be a strategy for circumventing tumor escape not only from the T cell-, but also the NK-cell mediated immune surveillance.

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