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Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tol...

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Autores principales: Noordam, Lisanne, Kaijen, Margaretha E.H., Bezemer, Koen, Cornelissen, Robin, Maat, Lex A.P.W.M., Hoogsteden, Henk C., Aerts, Joachim G.J.V., Hendriks, Rudi W., Hegmans, Joost P.J.J, Vroman, Heleen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Taylor & Francis 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279421/
https://www.ncbi.nlm.nih.gov/pubmed/30524884
http://dx.doi.org/10.1080/2162402X.2018.1474318
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author Noordam, Lisanne
Kaijen, Margaretha E.H.
Bezemer, Koen
Cornelissen, Robin
Maat, Lex A.P.W.M.
Hoogsteden, Henk C.
Aerts, Joachim G.J.V.
Hendriks, Rudi W.
Hegmans, Joost P.J.J
Vroman, Heleen
author_facet Noordam, Lisanne
Kaijen, Margaretha E.H.
Bezemer, Koen
Cornelissen, Robin
Maat, Lex A.P.W.M.
Hoogsteden, Henk C.
Aerts, Joachim G.J.V.
Hendriks, Rudi W.
Hegmans, Joost P.J.J
Vroman, Heleen
author_sort Noordam, Lisanne
collection PubMed
description Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients. Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry. Results: After one week treatment with mCTX, both activated FoxP3(hi) and naïve CD45RA(+) Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased. Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment.
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spelling pubmed-62794212018-12-06 Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy Noordam, Lisanne Kaijen, Margaretha E.H. Bezemer, Koen Cornelissen, Robin Maat, Lex A.P.W.M. Hoogsteden, Henk C. Aerts, Joachim G.J.V. Hendriks, Rudi W. Hegmans, Joost P.J.J Vroman, Heleen Oncoimmunology Original Research Rationale: Regulatory T cells (Treg) play a pivotal role in the immunosuppressive tumor micro-environment in cancer, including mesothelioma. Recently, the combination of autologous tumor lysate-pulsed dendritic cells (DC) and metronomic cyclophosphamide (mCTX) was reported as a feasible and well-tolerated treatment in malignant pleural mesothelioma patients and further as a method to reduce circulating Tregs. Objectives: The aim of this study was to establish the immunological effects of mCTX alone and in combination with DC-based immunotherapy on circulating Treg and other T cell subsets in mesothelioma patients. Methods: Ten patients received mCTX and DC-based immunotherapy after chemotherapy (n = 5) or chemotherapy and debulking surgery (n = 5). Peripheral blood mononuclear cells before, during and after treatment were analyzed for various Treg and other lymphocyte subsets by flow cytometry. Results: After one week treatment with mCTX, both activated FoxP3(hi) and naïve CD45RA(+) Tregs were effectively decreased in all patients. In addition, a shift from naïve and central memory towards effector memory and effector T cells was observed. Survival analysis showed that overall Treg levels before treatment were not correlated with survival, however, nTreg levels before treatment were positively correlated with survival. After completion of mCTX and DC-based immunotherapy treatment, all cell subsets returned to baseline levels, except for the proportions of proliferating EM CD8 T cells, which increased. Conclusions: mCTX treatment effectively reduced the proportions of circulating Tregs, both aTregs and nTregs, thereby favoring EM T cell subsets in mesothelioma patients. Interestingly, baseline levels of nTregs were positively correlated to overall survival upon complete treatment. Taylor & Francis 2018-07-30 /pmc/articles/PMC6279421/ /pubmed/30524884 http://dx.doi.org/10.1080/2162402X.2018.1474318 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
Noordam, Lisanne
Kaijen, Margaretha E.H.
Bezemer, Koen
Cornelissen, Robin
Maat, Lex A.P.W.M.
Hoogsteden, Henk C.
Aerts, Joachim G.J.V.
Hendriks, Rudi W.
Hegmans, Joost P.J.J
Vroman, Heleen
Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
title Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
title_full Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
title_fullStr Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
title_full_unstemmed Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
title_short Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
title_sort low-dose cyclophosphamide depletes circulating naïve and activated regulatory t cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279421/
https://www.ncbi.nlm.nih.gov/pubmed/30524884
http://dx.doi.org/10.1080/2162402X.2018.1474318
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