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Article Dans Une Revue Oncotarget Année : 2016

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

David Zucman
Claire Hivroz

Résumé

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 CD56(dim)CD16(pos) NK cells with otherwise normal expression of NK surface receptors. PD-1(pos) 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-1(pos) NK cells failed to degranulate and release IFN gamma, 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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Immunologie
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hal-01438166 , version 1 (30-10-2018)

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Asma Beldi-Ferchiou, Marion Lambert, Stephanie Dogniaux, Frederic Vely, Eric Vivier, et al.. PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma. Oncotarget, 2016, 7 (45), pp.72961-72977. ⟨10.18632/oncotarget.12150⟩. ⟨hal-01438166⟩
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