PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma
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Asma Beldi-Ferchiou1,2,11, Marion Lambert1,2, Stéphanie Dogniaux3, Frédéric Vély4,5, Eric Vivier4,5, Daniel Olive6, Stéphanie Dupuy1, Frank Levasseur1, David Zucman7, Céleste Lebbé8, Damien Sène1,2,9, Claire Hivroz4, Sophie Caillat-Zucman1,2,10
1Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l’Inflammation, Équipe Immunité Innée Chez l’enfant, Hôpital Robert Debré, Paris, France
2Université Paris Diderot, Sorbonne Paris Cité, Paris, France
3Institut Curie, Centre de Recherche, PSL Research University, INSERM U932 Immunité et Cancer, Paris, France
4Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, INSERM U1104, CNRS UMR7280, Marseille, France
5Immunologie, Hôpital de la Conception, Assistance Publique- Hôpitaux de Marseille, Marseille, France
6Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France
7Hôpital Foch, Service de Médecine Interne, Suresnes, France
8Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Département de Dermatologie, INSERM U976, Université Paris Diderot, Paris, France
9Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Département de Médecine Interne, Paris, France
10Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d’Immunologie, Paris, France
11Present address: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Henri Mondor, Laboratoire d’Immunologie, Créteil, France
Sophie Caillat-Zucman, email: email@example.com
Keywords: NK cells, Kaposi sarcoma, PD-1, immune checkpoint, tumor escape
Received: March 31, 2016 Accepted: September 13, 2016 Published: September 20, 2016
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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