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

Asma Beldi-Ferchiou,Marion Lambert,Stéphanie Dupuy,Frédéric Vély,Sophie Caillat-Zucman,Céleste Lebbé,Eric Vivier,David Zucman,Damien Sène,Claire Hivroz,Stéphanie Dogniaux,Frank Levasseur,Daniel Olive

doi:10.18632/oncotarget.12150

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.

Highlights

Natural Killer (NK) cells are cytotoxic innate lymphoid cells that are involved in the elimination of infected cells and tumors
We found that a subset of NK cells from Kaposi sarcoma (KS) patients expressed Programmed Death-1 (PD-1) (Figure 1A, 1B)
We found PD-1pos NK cells in HHV8 asymptomatic carriers, at two times lower frequency than in KS patients (2.0% ± 0.5% of NK cells, P = 0.01 compared to healthy controls; P = 0.02 compared to KS patients) (Figure 1B)

Summary

Introduction

Natural Killer (NK) cells are cytotoxic innate lymphoid cells that are involved in the elimination of infected cells and tumors. Reactivity of NK cells toward target cells is tightly regulated by the integration of signals from activating and inhibitory cell surface receptors, which determine the magnitude of NK cellmediated cytotoxicity and cytokine production [1,2,3,4]. NK cell activating receptors recognize stress-induced molecules at the surface of target cells, while inhibitory receptors mostly recognize major histocompatibility complex (MHC) class I molecules that contribute to host tolerance of NK cells. Target cells with low or no expression of MHC class I molecules do not provide inhibitory signals and become highly sensitive to NK cell-mediated elimination. Tumors and infected cells develop various escape strategies to bypass NK-cell mediated surveillance [8,9,10]

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