Identification of a subset of human natural killer cells expressing high levels of programmed death 1: A phenotypic and functional characterization.
Silvia Pesce,Marco Greppi,Giovanna Tabellini,Fabio Rampinelli,Silvia Parolini,Daniel Olive,Lorenzo Moretta,Alessandro Moretta,Emanuela Marcenaro +8 more
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TLDR
A novel subpopulation of human NK cells expressing high levels of PD‐1 is identified and characterized, which have the phenotypic characteristics of fully mature NK cells and are increased in patients with ovarian carcinoma.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-1 bright ) 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 CD56 dim but not CD56 bright NK cells and is confined to fully mature NK cells characterized by the NKG2A − KIR + CD57 + phenotype. Proportions of PD-1 bright 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.read more
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New miRNA Signature Heralds Human NK Cell Subsets at Different Maturation Steps: Involvement of miR-146a-5p in the Regulation of KIR Expression.
Silvia Pesce,Margherita Squillario,Marco Greppi,Fabrizio Loiacono,Lorenzo Moretta,Alessandro Moretta,Simona Sivori,Patrizio Castagnola,Annalisa Barla,Simona Candiani,Emanuela Marcenaro +10 more
TL;DR: The results suggest that hsa-miR-146a-5p targeting, resulting in KIR down-regulation, may be exploited to generate/increment the effect of NK KIR-mismatching against HLA-class I+ tumor cells and thus improve the NK-mediated anti-tumor activity.
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The immune landscape of common CNS malignancies: implications for immunotherapy.
TL;DR: This article reviewed the emerging data on the differences in immune cell composition, function and interactions within central nervous system tumours and provided guidance on the development of novel immunotherapies for these historically difficult-to-treat cancers.
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Modulation of NK cells with checkpoint inhibitors in the context of cancer immunotherapy
Beatriz Sanchez-Correa,Nelson Lopez-Sejas,Esther Duran,Fernando Labella,Corona Alonso,Rafael Solana,Rafael Solana,Raquel Tarazona +7 more
TL;DR: The identification of NK cell and tumour cell markers of resistance or susceptibility to the action of NK cells will contribute to identifying those patients that will most likely benefit from NK cell-based immunotherapy.
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Harnessing natural killer cells for cancer immunotherapy: dispatching the first responders
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Human NK Cell Subsets Redistribution in Pathological Conditions: A Role for CCR7 Receptor
TL;DR: Recent progress in understanding the mechanisms and the site where CD56dim KIR+ NK cells can acquire the capability to migrate toward lymph nodes is described and the emerging significance of this event in clinical transplantation is discussed.
References
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PD-1 and its ligands in tolerance and immunity
TL;DR: Current understanding of the immunoregulatory functions of PD-1 and its ligands and their therapeutic potential are discussed and an inhibitory bidirectional interaction between PD-L1 and B7-1 is discovered, revealing new ways the B7:CD28 family regulates T cell activation and tolerance.
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TL;DR: Conurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.
Journal ArticleDOI
Restoring function in exhausted CD8 T cells during chronic viral infection.
Daniel L. Barber,E. John Wherry,David Masopust,Baogong Zhu,James P. Allison,Arlene H. Sharpe,Gordon J. Freeman,Rafi Ahmed +7 more
TL;DR: In this article, the authors analyzed genes expressed in functionally impaired virus-specific CD8 T cells present in mice chronically infected with lymphocytic choriomeningitis virus (LCMV), and compared these with the gene profile of functional memory CD8T cells.
Journal Article
Restoring function in exhausted CD8 T cells during chronic viral infection
TL;DR: It is found that even in persistently infected mice that were lacking CD4 T-cell help, blockade of the PD-1/PD-L1 inhibitory pathway had a beneficial effect on the ‘helpless’ CD8 T cells, restoring their ability to undergo proliferation, secrete cytokines, kill infected cells and decrease viral load.
Journal ArticleDOI
Activation of NK Cells and T Cells by NKG2D, a Receptor for Stress-Inducible MICA
Stefan Bauer,Veronika Groh,Jun Wu,Alexander Steinle,Joseph H. Phillips,Lewis L. Lanier,Thomas Spies +6 more
TL;DR: An activating immunoreceptor-MHC ligand interaction that may promote antitumor NK and T cell responses is defined.
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