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

Abstract

// Asma Beldi-Ferchiou 1, 2, 11 , Marion Lambert 1, 2 , Stéphanie Dogniaux 3 , Frédéric Vély 4, 5 , Eric Vivier 4, 5 , Daniel Olive 6 , Stéphanie Dupuy 1 , Frank Levasseur 1 , David Zucman 7 , Céleste Lebbé 8 , Damien Sène 1, 2, 9 , Claire Hivroz 4 , Sophie Caillat-Zucman 1, 2, 10 1 Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l’Inflammation, Équipe Immunité Innée Chez l’enfant, Hôpital Robert Debré, Paris, France 2 Université Paris Diderot, Sorbonne Paris Cité, Paris, France 3 Institut Curie, Centre de Recherche, PSL Research University, INSERM U932 Immunité et Cancer, Paris, France 4 Centre d’Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, INSERM U1104, CNRS UMR7280, Marseille, France 5 Immunologie, Hôpital de la Conception, Assistance Publique- Hôpitaux de Marseille, Marseille, France 6 Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France 7 Hôpital Foch, Service de Médecine Interne, Suresnes, France 8 Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Département de Dermatologie, INSERM U976, Université Paris Diderot, Paris, France 9 Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Département de Médecine Interne, Paris, France 10 Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d’Immunologie, Paris, France 11 Present address: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Henri Mondor, Laboratoire d’Immunologie, Créteil, France Correspondence to: Sophie Caillat-Zucman, email: sophie.caillat@inserm.fr Keywords: NK cells, Kaposi sarcoma, PD-1, immune checkpoint, tumor escape Received: March 31, 2016      Accepted: September 13, 2016      Published: September 20, 2016 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 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 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.