Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783366716936421376 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6208452 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT mesianogiulia cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT grignanigiovanni cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT fiorinoerika cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT leucivaleria cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT rotoloramona cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT dambrosiolorenzo cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT salfichiara cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT gammaitoniloretta cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT giraudolidia cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT pisacanealberto cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT buterasara cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT pignochinoymera cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT basiricomarco cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT capozzifederica cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT sapinoanna cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT agliettamassimo cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy AT sangiolodario cytokineinducedkillercellsareeffectiveagainstsarcomacancerstemcellssparedbychemotherapyandtargettherapy |