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Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality

In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known...

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Autores principales: Khaleafi, Raghad, Zeleznjak, Jelena, Cordela, Sapir, Drucker, Shani, Rovis, Tihana Lenac, Jonjic, Stipan, Bar-On, Yotam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518469/
https://www.ncbi.nlm.nih.gov/pubmed/37753084
http://dx.doi.org/10.3389/fimmu.2023.1231782
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author Khaleafi, Raghad
Zeleznjak, Jelena
Cordela, Sapir
Drucker, Shani
Rovis, Tihana Lenac
Jonjic, Stipan
Bar-On, Yotam
author_facet Khaleafi, Raghad
Zeleznjak, Jelena
Cordela, Sapir
Drucker, Shani
Rovis, Tihana Lenac
Jonjic, Stipan
Bar-On, Yotam
author_sort Khaleafi, Raghad
collection PubMed
description In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how reovirus infection affects the tumor microenvironment and immune response towards infected tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular ligands on tumor cells, which are ultimately key to tumor recognition and elimination by NK cells, has not been investigated. We tested how reovirus infection affects the binding of the NK Group-2 member D (NKG2D) receptor, which is a dominant mediator of NK cell anti-tumor activity. Using models of human-derived melanoma and glioblastoma tumors, we demonstrated that NKG2D ligands are downregulated in tumor cells post-reovirus-infection due to the impaired translation of these ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D ligands significantly impaired the binding of NKG2D to infected tumor cells. We further demonstrated that reduced recognition of NKG2D ligands significantly alters NK cell anti-tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based therapeutics that enhance the anti-tumor immune response.
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spelling pubmed-105184692023-09-26 Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality Khaleafi, Raghad Zeleznjak, Jelena Cordela, Sapir Drucker, Shani Rovis, Tihana Lenac Jonjic, Stipan Bar-On, Yotam Front Immunol Immunology In recent years, reoviruses have been of major interest in immunotherapy because of their oncolytic properties. Preclinical and clinical trials, in which reovirus was used for the treatment of melanoma and glioblastoma, have paved the way for future clinical use of reovirus. However, little is known about how reovirus infection affects the tumor microenvironment and immune response towards infected tumor cells. Studies have shown that reovirus can directly stimulate natural killer (NK) cells, but how reovirus affects cellular ligands on tumor cells, which are ultimately key to tumor recognition and elimination by NK cells, has not been investigated. We tested how reovirus infection affects the binding of the NK Group-2 member D (NKG2D) receptor, which is a dominant mediator of NK cell anti-tumor activity. Using models of human-derived melanoma and glioblastoma tumors, we demonstrated that NKG2D ligands are downregulated in tumor cells post-reovirus-infection due to the impaired translation of these ligands in reovirus-infected cells. Moreover, we showed that downregulation of NKG2D ligands significantly impaired the binding of NKG2D to infected tumor cells. We further demonstrated that reduced recognition of NKG2D ligands significantly alters NK cell anti-tumor cytotoxicity in human primary NK cells and in the NK cell line NK-92. Thus, this study provides novel insights into reovirus-host interactions and could lead to the development of novel reovirus-based therapeutics that enhance the anti-tumor immune response. Frontiers Media S.A. 2023-09-11 /pmc/articles/PMC10518469/ /pubmed/37753084 http://dx.doi.org/10.3389/fimmu.2023.1231782 Text en Copyright © 2023 Khaleafi, Zeleznjak, Cordela, Drucker, Rovis, Jonjic and Bar-On https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Khaleafi, Raghad
Zeleznjak, Jelena
Cordela, Sapir
Drucker, Shani
Rovis, Tihana Lenac
Jonjic, Stipan
Bar-On, Yotam
Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality
title Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality
title_full Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality
title_fullStr Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality
title_full_unstemmed Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality
title_short Reovirus infection of tumor cells reduces the expression of NKG2D ligands, leading to impaired NK-cell cytotoxicity and functionality
title_sort reovirus infection of tumor cells reduces the expression of nkg2d ligands, leading to impaired nk-cell cytotoxicity and functionality
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10518469/
https://www.ncbi.nlm.nih.gov/pubmed/37753084
http://dx.doi.org/10.3389/fimmu.2023.1231782
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