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Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.

Metastatic bone and soft tissue sarcomas often relapse after chemotherapy (CHT) and molecular targeted therapy (mTT), maintaining a severe prognosis. A subset of sarcoma cancer stem cells (sCSC) is hypothesized to resist conventional drugs and sustain disease relapses. We investigated the immunother...

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Autores principales: Mesiano, Giulia, Grignani, Giovanni, Fiorino, Erika, Leuci, Valeria, Rotolo, Ramona, D’Ambrosio, Lorenzo, Salfi, Chiara, Gammaitoni, Loretta, Giraudo, Lidia, Pisacane, Alberto, Butera, Sara, Pignochino, Ymera, Basiricó, Marco, Capozzi, Federica, Sapino, Anna, Aglietta, Massimo, Sangiolo, Dario
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208452/
https://www.ncbi.nlm.nih.gov/pubmed/30393581
http://dx.doi.org/10.1080/2162402X.2018.1465161
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author Mesiano, Giulia
Grignani, Giovanni
Fiorino, Erika
Leuci, Valeria
Rotolo, Ramona
D’Ambrosio, Lorenzo
Salfi, Chiara
Gammaitoni, Loretta
Giraudo, Lidia
Pisacane, Alberto
Butera, Sara
Pignochino, Ymera
Basiricó, Marco
Capozzi, Federica
Sapino, Anna
Aglietta, Massimo
Sangiolo, Dario
author_facet Mesiano, Giulia
Grignani, Giovanni
Fiorino, Erika
Leuci, Valeria
Rotolo, Ramona
D’Ambrosio, Lorenzo
Salfi, Chiara
Gammaitoni, Loretta
Giraudo, Lidia
Pisacane, Alberto
Butera, Sara
Pignochino, Ymera
Basiricó, Marco
Capozzi, Federica
Sapino, Anna
Aglietta, Massimo
Sangiolo, Dario
author_sort Mesiano, Giulia
collection PubMed
description Metastatic bone and soft tissue sarcomas often relapse after chemotherapy (CHT) and molecular targeted therapy (mTT), maintaining a severe prognosis. A subset of sarcoma cancer stem cells (sCSC) is hypothesized to resist conventional drugs and sustain disease relapses. We investigated the immunotherapy activity of cytokine induced killer cells (CIK) against autologous sCSC that survived CHT and mTT. The experimental platform included two aggressive bone and soft tissue sarcoma models: osteosarcoma (OS) and undifferentiated-pleomorphic sarcoma (UPS). To visualize putative sCSC we engineered patient-derived sarcoma cultures (2 OS and 3 UPS) with a lentiviral sCSC-detector wherein the promoter of stem-gene Oct4 controls the expression of eGFP. We visualized a fraction of sCSC (mean 24.2 ± 5.2%) and confirmed their tumorigenicity in vivo. sCSC resulted relatively resistant to both CHT and mTT in vitro. Therapeutic doses of doxorubicin significantly enriched viable eGFP(+)sCSC in both OS (2.6 fold, n = 16) and UPS (2.3 fold, n = 29) compared to untreated controls. Treatment with sorafenib (for OS) and pazopanib (for UPS) also determined enrichment (1.3 fold) of viable eGFP(+)sCSC, even if less intense than what observed after CHT. Sarcoma cells surviving CHT and mTT were efficiently killed in vitro by autologous CIK even at minimal effector/target ratios (40:1 = 82%, 1:4 = 29%, n = 13). CIK immunotherapy did not spare sCSC that were killed as efficiently as whole sarcoma cell population. The relative chemo-resistance of sCSC and sensitivity to CIK immunotherapy was confirmed in vivo. Our findings support CIK as an innovative, clinically explorable, approach to eradicate chemo-resistant sCSC implicated in tumor relapse.
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spelling pubmed-62084522018-11-02 Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy. Mesiano, Giulia Grignani, Giovanni Fiorino, Erika Leuci, Valeria Rotolo, Ramona D’Ambrosio, Lorenzo Salfi, Chiara Gammaitoni, Loretta Giraudo, Lidia Pisacane, Alberto Butera, Sara Pignochino, Ymera Basiricó, Marco Capozzi, Federica Sapino, Anna Aglietta, Massimo Sangiolo, Dario Oncoimmunology Original Research Metastatic bone and soft tissue sarcomas often relapse after chemotherapy (CHT) and molecular targeted therapy (mTT), maintaining a severe prognosis. A subset of sarcoma cancer stem cells (sCSC) is hypothesized to resist conventional drugs and sustain disease relapses. We investigated the immunotherapy activity of cytokine induced killer cells (CIK) against autologous sCSC that survived CHT and mTT. The experimental platform included two aggressive bone and soft tissue sarcoma models: osteosarcoma (OS) and undifferentiated-pleomorphic sarcoma (UPS). To visualize putative sCSC we engineered patient-derived sarcoma cultures (2 OS and 3 UPS) with a lentiviral sCSC-detector wherein the promoter of stem-gene Oct4 controls the expression of eGFP. We visualized a fraction of sCSC (mean 24.2 ± 5.2%) and confirmed their tumorigenicity in vivo. sCSC resulted relatively resistant to both CHT and mTT in vitro. Therapeutic doses of doxorubicin significantly enriched viable eGFP(+)sCSC in both OS (2.6 fold, n = 16) and UPS (2.3 fold, n = 29) compared to untreated controls. Treatment with sorafenib (for OS) and pazopanib (for UPS) also determined enrichment (1.3 fold) of viable eGFP(+)sCSC, even if less intense than what observed after CHT. Sarcoma cells surviving CHT and mTT were efficiently killed in vitro by autologous CIK even at minimal effector/target ratios (40:1 = 82%, 1:4 = 29%, n = 13). CIK immunotherapy did not spare sCSC that were killed as efficiently as whole sarcoma cell population. The relative chemo-resistance of sCSC and sensitivity to CIK immunotherapy was confirmed in vivo. Our findings support CIK as an innovative, clinically explorable, approach to eradicate chemo-resistant sCSC implicated in tumor relapse. Taylor & Francis 2018-08-06 /pmc/articles/PMC6208452/ /pubmed/30393581 http://dx.doi.org/10.1080/2162402X.2018.1465161 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
Mesiano, Giulia
Grignani, Giovanni
Fiorino, Erika
Leuci, Valeria
Rotolo, Ramona
D’Ambrosio, Lorenzo
Salfi, Chiara
Gammaitoni, Loretta
Giraudo, Lidia
Pisacane, Alberto
Butera, Sara
Pignochino, Ymera
Basiricó, Marco
Capozzi, Federica
Sapino, Anna
Aglietta, Massimo
Sangiolo, Dario
Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
title Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
title_full Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
title_fullStr Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
title_full_unstemmed Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
title_short Cytokine Induced Killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
title_sort cytokine induced killer cells are effective against sarcoma cancer stem cells spared by chemotherapy and target therapy.
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208452/
https://www.ncbi.nlm.nih.gov/pubmed/30393581
http://dx.doi.org/10.1080/2162402X.2018.1465161
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