Cargando…
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...
Autores principales: | , , , , , , , , , |
---|---|
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 |
_version_ | 1783378502915981312 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6279421 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Taylor & Francis |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT noordamlisanne lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT kaijenmargarethaeh lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT bezemerkoen lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT cornelissenrobin lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT maatlexapwm lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT hoogstedenhenkc lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT aertsjoachimgjv lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT hendriksrudiw lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT hegmansjoostpjj lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy AT vromanheleen lowdosecyclophosphamidedepletescirculatingnaiveandactivatedregulatorytcellsinmalignantpleuralmesotheliomapatientssynergisticallytreatedwithdendriticcellbasedimmunotherapy |