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Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D

Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but...

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Autores principales: Sayitoglu, Ece Canan, Georgoudaki, Anna-Maria, Chrobok, Michael, Ozkazanc, Didem, Josey, Benjamin J., Arif, Muhammad, Kusser, Kim, Hartman, Michelle, Chinn, Tamara M., Potens, Renee, Pamukcu, Cevriye, Krueger, Robin, Zhang, Cheng, Mardinoglu, Adil, Alici, Evren, Temple, Harry Thomas, Sutlu, Tolga, Duru, Adil Doganay
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001093/
https://www.ncbi.nlm.nih.gov/pubmed/32082316
http://dx.doi.org/10.3389/fimmu.2020.00040
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author Sayitoglu, Ece Canan
Georgoudaki, Anna-Maria
Chrobok, Michael
Ozkazanc, Didem
Josey, Benjamin J.
Arif, Muhammad
Kusser, Kim
Hartman, Michelle
Chinn, Tamara M.
Potens, Renee
Pamukcu, Cevriye
Krueger, Robin
Zhang, Cheng
Mardinoglu, Adil
Alici, Evren
Temple, Harry Thomas
Sutlu, Tolga
Duru, Adil Doganay
author_facet Sayitoglu, Ece Canan
Georgoudaki, Anna-Maria
Chrobok, Michael
Ozkazanc, Didem
Josey, Benjamin J.
Arif, Muhammad
Kusser, Kim
Hartman, Michelle
Chinn, Tamara M.
Potens, Renee
Pamukcu, Cevriye
Krueger, Robin
Zhang, Cheng
Mardinoglu, Adil
Alici, Evren
Temple, Harry Thomas
Sutlu, Tolga
Duru, Adil Doganay
author_sort Sayitoglu, Ece Canan
collection PubMed
description Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1(+) or NKG2D(+) GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1(+) or NKG2D(+) GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1(+) or NKG2D(+) GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.
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spelling pubmed-70010932020-02-20 Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D Sayitoglu, Ece Canan Georgoudaki, Anna-Maria Chrobok, Michael Ozkazanc, Didem Josey, Benjamin J. Arif, Muhammad Kusser, Kim Hartman, Michelle Chinn, Tamara M. Potens, Renee Pamukcu, Cevriye Krueger, Robin Zhang, Cheng Mardinoglu, Adil Alici, Evren Temple, Harry Thomas Sutlu, Tolga Duru, Adil Doganay Front Immunol Immunology Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1(+) or NKG2D(+) GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1(+) or NKG2D(+) GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1(+) or NKG2D(+) GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies. Frontiers Media S.A. 2020-01-28 /pmc/articles/PMC7001093/ /pubmed/32082316 http://dx.doi.org/10.3389/fimmu.2020.00040 Text en Copyright © 2020 Sayitoglu, Georgoudaki, Chrobok, Ozkazanc, Josey, Arif, Kusser, Hartman, Chinn, Potens, Pamukcu, Krueger, Zhang, Mardinoglu, Alici, Temple, Sutlu and Duru. http://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
Sayitoglu, Ece Canan
Georgoudaki, Anna-Maria
Chrobok, Michael
Ozkazanc, Didem
Josey, Benjamin J.
Arif, Muhammad
Kusser, Kim
Hartman, Michelle
Chinn, Tamara M.
Potens, Renee
Pamukcu, Cevriye
Krueger, Robin
Zhang, Cheng
Mardinoglu, Adil
Alici, Evren
Temple, Harry Thomas
Sutlu, Tolga
Duru, Adil Doganay
Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
title Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
title_full Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
title_fullStr Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
title_full_unstemmed Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
title_short Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D
title_sort boosting natural killer cell-mediated targeting of sarcoma through dnam-1 and nkg2d
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001093/
https://www.ncbi.nlm.nih.gov/pubmed/32082316
http://dx.doi.org/10.3389/fimmu.2020.00040
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