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Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction

Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppress...

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Autores principales: Idorn, Manja, Olsen, Maria, Halldórsdóttir, Hólmfrídur Rósa, Skadborg, Signe Koggersbøl, Pedersen, Magnus, Høgdall, Claus, Høgdall, Estrid, Met, Özcan, thor Straten, Per
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889291/
https://www.ncbi.nlm.nih.gov/pubmed/29632724
http://dx.doi.org/10.1080/2162402X.2017.1412029
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author Idorn, Manja
Olsen, Maria
Halldórsdóttir, Hólmfrídur Rósa
Skadborg, Signe Koggersbøl
Pedersen, Magnus
Høgdall, Claus
Høgdall, Estrid
Met, Özcan
thor Straten, Per
author_facet Idorn, Manja
Olsen, Maria
Halldórsdóttir, Hólmfrídur Rósa
Skadborg, Signe Koggersbøl
Pedersen, Magnus
Høgdall, Claus
Høgdall, Estrid
Met, Özcan
thor Straten, Per
author_sort Idorn, Manja
collection PubMed
description Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were analyzed by flow cytometry. We found that FoxP3(+) regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22, CXCL9, CXCL10 and CXCL12 associated with enrichment of CCR4(+), CCR5(+), CXCR3(+) and CXCR4(+) T cells in ascites. Circulating T cells and TALs however did not express CXCR2, identifying CXCR2 as candidate for chemokine receptor transduction. TALs readily expressed IFNγ and TNFα upon stimulation despite the frequency decreasing with in vitro expansion. Lentiviral transduction of TALs (n = 4) with chemokine receptor CXCR2 significantly increased transwell migration of TALs towards rhIL8 and autologous ascites. The majority of expanded and transduced TALs were of a T effector memory subtype. This proof of concept study shows that chemokine receptor engineering with CXCR2 is feasible and improves homing of transduced TALs towards the OC microenvironment.
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spelling pubmed-58892912018-04-09 Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction Idorn, Manja Olsen, Maria Halldórsdóttir, Hólmfrídur Rósa Skadborg, Signe Koggersbøl Pedersen, Magnus Høgdall, Claus Høgdall, Estrid Met, Özcan thor Straten, Per Oncoimmunology Original Research Chemokines are essential mediators of cellular trafficking, interactions and tumor development. Though adoptive cell therapy (ACT) has been a tremendous success in the treatment of metastatic melanoma (MM), a major obstacle for successful ACT, is limited homing of effector T cells to immune suppressive tumor sites. We hypothesized that equipping T cells with chemokine receptors matching the chemokines of the tumor microenvironment, could improve tumor homing of T cells. T cells from malignant ascites (n = 13); blood from ovarian cancer (OC) patients (n = 14); and healthy donors (n = 13) were analyzed by flow cytometry. We found that FoxP3(+) regulatory T cells accumulation in patients with OC associates with CCR4 expression. We characterized a chemokine profile of ascites chemokines, and expression of corresponding receptors on circulating T cells and tumor ascites lymphocytes (TALs). CCL22, CXCL9, CXCL10 and CXCL12 associated with enrichment of CCR4(+), CCR5(+), CXCR3(+) and CXCR4(+) T cells in ascites. Circulating T cells and TALs however did not express CXCR2, identifying CXCR2 as candidate for chemokine receptor transduction. TALs readily expressed IFNγ and TNFα upon stimulation despite the frequency decreasing with in vitro expansion. Lentiviral transduction of TALs (n = 4) with chemokine receptor CXCR2 significantly increased transwell migration of TALs towards rhIL8 and autologous ascites. The majority of expanded and transduced TALs were of a T effector memory subtype. This proof of concept study shows that chemokine receptor engineering with CXCR2 is feasible and improves homing of transduced TALs towards the OC microenvironment. Taylor & Francis 2017-12-26 /pmc/articles/PMC5889291/ /pubmed/29632724 http://dx.doi.org/10.1080/2162402X.2017.1412029 Text en © 2018 The Author(s). Published with license by Taylor & Francis Group, LLC http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
spellingShingle Original Research
Idorn, Manja
Olsen, Maria
Halldórsdóttir, Hólmfrídur Rósa
Skadborg, Signe Koggersbøl
Pedersen, Magnus
Høgdall, Claus
Høgdall, Estrid
Met, Özcan
thor Straten, Per
Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
title Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
title_full Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
title_fullStr Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
title_full_unstemmed Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
title_short Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction
title_sort improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by cxcr2 transduction
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889291/
https://www.ncbi.nlm.nih.gov/pubmed/29632724
http://dx.doi.org/10.1080/2162402X.2017.1412029
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