PD-1 mediates functional exhaustion of activated NK cells in patients with Kaposi sarcoma.
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.
Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l'Inflammation, Équipe Immunité Innée Chez l'Enfant, Hôpital Robert Debré, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Present address: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Henri Mondor, Laboratoire d'Immunologie, Créteil, France.
Asma
A
Beldi-Ferchiou
Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l'Inflammation, Équipe Immunité Innée Chez l'Enfant, Hôpital Robert Debré, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.
Marion
M
Lambert
Institut Curie, Centre de Recherche, PSL Research University, INSERM U932 Immunité et Cancer, Paris, France.
Stéphanie
S
Dogniaux
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, INSERM U1104, CNRS UMR7280, Marseille, France.|Immunologie, Hôpital de la Conception, Assistance Publique- Hôpitaux de Marseille, Marseille, France.
Frédéric
F
Vély
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, INSERM U1104, CNRS UMR7280, Marseille, France.|Immunologie, Hôpital de la Conception, Assistance Publique- Hôpitaux de Marseille, Marseille, France.
Eric
E
Vivier
Centre de Cancérologie de Marseille, INSERM U1068, Equipe Immunité et Cancer, Institut Paoli-Calmettes, Aix-Marseille Université, CNRS, UMR7258, Marseille, France.
Daniel
D
Olive
Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l'Inflammation, Équipe Immunité Innée Chez l'Enfant, Hôpital Robert Debré, Paris, France.
Stéphanie
S
Dupuy
Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l'Inflammation, Équipe Immunité Innée Chez l'Enfant, Hôpital Robert Debré, Paris, France.
Frank
F
Levasseur
Hôpital Foch, Service de Médecine Interne, Suresnes, France.
David
D
Zucman
Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Département de Dermatologie, INSERM U976, Université Paris Diderot, Paris, France.
Céleste
C
Lebbé
Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l'Inflammation, Équipe Immunité Innée Chez l'Enfant, Hôpital Robert Debré, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Lariboisière, Département de Médecine Interne, Paris, France.
Damien
D
Sène
Centre d'Immunologie de Marseille-Luminy, Aix-Marseille Université UM2, INSERM U1104, CNRS UMR7280, Marseille, France.
Claire
C
Hivroz
Institut National de Recherche Médicale (INSERM) UMR1149, Centre de Recherche Sur l'Inflammation, Équipe Immunité Innée Chez l'Enfant, Hôpital Robert Debré, Paris, France.|Université Paris Diderot, Sorbonne Paris Cité, Paris, France.|Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie, Paris, France.
Sophie
S
Caillat-Zucman
D015415:Biomarkers; D016022:Case-Control Studies; D060085:Coinfection; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D015870:Gene Expression; D015658:HIV Infections / Q000150:complications / Q000821:virology; D006526:Hepatitis C / Q000150:complications / Q000821:virology; D006566:Herpesviridae Infections / Q000150:complications / Q000821:virology; D019288:Herpesvirus 8, Human; D006801:Humans; D007150:Immunohistochemistry; D056747:Immunomodulation; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D010641:Phenotype; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*; D012514:Sarcoma, Kaposi / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology
D015415:Biomarkers; D016207:Cytokines; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor
Kaposi sarcoma; NK cells; PD-1; immune checkpoint; tumor escape
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