Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization

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• 作者：Silvia Pesce ; PhD^a ; Marco Greppi^a ; Giovanna Tabellini ; PhD^b ; Fabio Rampinelli ; MD^c ; Silvia Parolini ; PhD^b ; Daniel Olive ; MD^d ; Lorenzo Moretta ; MD^e ; Alessandro Moretta ; MD^a ; ^f ; ^&lowast ; ; ^{alemoret@unige.it} ; Emanuela Marcenaro ; PhD^a ; ^f ; ^&lowast ;
• 关键词：Natural killer cells ; programmed death receptor ; ovarian carcinoma ; tumor escape ; immune checkpoint ; natural killer cell degranulation ; natural killer cell proliferation ; natural killer cell cytokine production ; CD57+ natural killer cells ; cytomegalovirus
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：139
• 期：1
• 页码：335-346.e3
• 全文大小：3300 K
• 卷排序：139

文摘

Programmed death 1 (PD-1) is an immunologic checkpoint that limits immune responses by delivering potent inhibitory signals to T cells on interaction with specific ligands expressed on tumor/virus-infected cells, thus contributing to immune escape mechanisms. Therapeutic PD-1 blockade has been shown to mediate tumor eradication with impressive clinical results. Little is known about the expression/function of PD-1 on human natural killer (NK) cells.ObjectiveWe sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features.MethodsWe performed multiparametric cytofluorimetric analysis of PD-1+ NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays.ResultsWe provide unequivocal evidence that PD-1 is highly expressed (PD-1bright) on an NK cell subset detectable in the peripheral blood of approximately one fourth of healthy subjects. These donors are always serologically positive for human cytomegalovirus. PD-1 is expressed by CD56dim but not CD56bright NK cells and is confined to fully mature NK cells characterized by the NKG2A−KIR+CD57+ phenotype. Proportions of PD-1bright NK cells were higher in the ascites of a cohort of patients with ovarian carcinoma, suggesting their possible induction/expansion in tumor environments. Functional analysis revealed a reduced proliferative capability in response to cytokines, low degranulation, and impaired cytokine production on interaction with tumor targets.ConclusionsWe have identified and characterized a novel subpopulation of human NK cells expressing high levels of PD-1. These cells have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma. They display low proliferative responses and impaired antitumor activity that can be partially restored by antibody-mediated disruption of PD-1/programmed death ligand interaction.