Silvia Pesce1, Marco Greppi1, Giovanna Tabellini2, Fabio Rampinelli3, Silvia Parolini2, Daniel Olive4, Lorenzo Moretta5, Alessandro Moretta6, Emanuela Marcenaro7. 1. Department of Experimental Medicine, University of Genoa, Genoa, Italy. 2. Department of Molecular and Translational Medicine, Brescia, Italy. 3. Department of Obstetrics and Gynecology, Spedali Civili of Brescia, Brescia, Italy. 4. CRCM, Equipe Immunité et Cancer, Inserm, U1068, Institut Paoli-Calmettes, Aix-Marseille Université, Marseille, France. 5. Department of Immunology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. 6. Department of Experimental Medicine, University of Genoa, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy. Electronic address: alemoret@unige.it. 7. Department of Experimental Medicine, University of Genoa, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), University of Genoa, Genoa, Italy.
Abstract
BACKGROUND: 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. OBJECTIVE: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. METHODS: We performed multiparametric cytofluorimetric analysis of PD-1+ NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. RESULTS: We 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. CONCLUSIONS: We 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.
BACKGROUND: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. OBJECTIVE: We sought to clarify whether human NK cells can express PD-1 and analyze their phenotypic/functional features. METHODS: We performed multiparametric cytofluorimetric analysis of PD-1+ NK cells and their functional characterization using degranulation, cytokine production, and proliferation assays. RESULTS: We 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. CONCLUSIONS: We 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.
Authors: Pulak Ranjan Nath; Dipasmita Pal-Nath; Ajeet Mandal; Margaret C Cam; Anthony L Schwartz; David D Roberts Journal: Cancer Immunol Res Date: 2019-07-30 Impact factor: 11.151
Authors: Wenjuan Dong; Xiaojin Wu; Shoubao Ma; Yufeng Wang; Ansel P Nalin; Zheng Zhu; Jianying Zhang; Don M Benson; Kai He; Michael A Caligiuri; Jianhua Yu Journal: Cancer Discov Date: 2019-07-24 Impact factor: 39.397
Authors: Joy Hsu; Jonathan J Hodgins; Malvika Marathe; Chris J Nicolai; Marie-Claude Bourgeois-Daigneault; Troy N Trevino; Camillia S Azimi; Amit K Scheer; Haley E Randolph; Thornton W Thompson; Lily Zhang; Alexandre Iannello; Nikhita Mathur; Karen E Jardine; Georgia A Kirn; John C Bell; Michael W McBurney; David H Raulet; Michele Ardolino Journal: J Clin Invest Date: 2018-09-10 Impact factor: 14.808
Authors: Fernando Concha-Benavente; Benjamin Kansy; Jessica Moskovitz; Jennifer Moy; Uma Chandran; Robert L Ferris Journal: Cancer Immunol Res Date: 2018-10-03 Impact factor: 11.151