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Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor

Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characte...

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Autores principales: Di Pace, Anna Laura, Tumino, Nicola, Besi, Francesca, Alicata, Claudia, Conti, Libenzio Adrian, Munari, Enrico, Maggi, Enrico, Vacca, Paola, Moretta, Lorenzo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140072/
https://www.ncbi.nlm.nih.gov/pubmed/32178479
http://dx.doi.org/10.3390/cancers12030661
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author Di Pace, Anna Laura
Tumino, Nicola
Besi, Francesca
Alicata, Claudia
Conti, Libenzio Adrian
Munari, Enrico
Maggi, Enrico
Vacca, Paola
Moretta, Lorenzo
author_facet Di Pace, Anna Laura
Tumino, Nicola
Besi, Francesca
Alicata, Claudia
Conti, Libenzio Adrian
Munari, Enrico
Maggi, Enrico
Vacca, Paola
Moretta, Lorenzo
author_sort Di Pace, Anna Laura
collection PubMed
description Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes.
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spelling pubmed-71400722020-04-13 Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor Di Pace, Anna Laura Tumino, Nicola Besi, Francesca Alicata, Claudia Conti, Libenzio Adrian Munari, Enrico Maggi, Enrico Vacca, Paola Moretta, Lorenzo Cancers (Basel) Article Despite the pivotal role of natural killer (NK) cells in defenses against tumors, their exploitation in cancer treatment is still limited due to their reduced ability to reaching tumor sites and the inhibitory effects of tumor microenvironment (TME) on their function. In this study, we have characterized the exosomes from IL2- or IL15-cultured human NK cells. Both cytokines induced comparable amounts of exosomes with similar cargo composition. Analysis of molecules contained within or exposed at the exosome surface, allowed the identification of molecules playing important roles in the NK cell function including IFN-γ, Lymphocyte Function-Associated Antigen (LFA-1), DNAX Accessory Molecule-1 (DNAM1) and Programmed Cell Death Protein (PD-1). Importantly, we show that DNAM1 is involved in exosome-mediated cytotoxicity as revealed by experiments using blocking antibodies to DNAM1 or DNAM1 ligands. In addition, antibody-mediated inhibition of exosome cytotoxicity results in a delay in target cell apoptosis. We also provide evidence that NK-exosomes may exert their cytolytic activity after short time interval and even at low concentrations. Regarding their possible use in immunotherapy, NK exosomes, detectable in peripheral blood, can diffuse into tissues and exert their cytolytic effect at tumor sites. This property offers a clue to integrate cancer treatments with NK exosomes. MDPI 2020-03-12 /pmc/articles/PMC7140072/ /pubmed/32178479 http://dx.doi.org/10.3390/cancers12030661 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Di Pace, Anna Laura
Tumino, Nicola
Besi, Francesca
Alicata, Claudia
Conti, Libenzio Adrian
Munari, Enrico
Maggi, Enrico
Vacca, Paola
Moretta, Lorenzo
Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
title Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
title_full Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
title_fullStr Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
title_full_unstemmed Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
title_short Characterization of Human NK Cell-Derived Exosomes: Role of DNAM1 Receptor in Exosome-Mediated Cytotoxicity against Tumor
title_sort characterization of human nk cell-derived exosomes: role of dnam1 receptor in exosome-mediated cytotoxicity against tumor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7140072/
https://www.ncbi.nlm.nih.gov/pubmed/32178479
http://dx.doi.org/10.3390/cancers12030661
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