Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response
Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) com...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-02-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396420305363 |
| _version_ | 1818580405655175168 |
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| author | Floris Dammeijer Cornedine J. De Gooijer Mandy van Gulijk Melanie Lukkes Larissa Klaase Lysanne A. Lievense Cynthia Waasdorp Merel Jebbink Gerben P. Bootsma Jos A. Stigt Bonne Biesma Margaretha E.H. Kaijen-Lambers Joanne Mankor Heleen Vroman Robin Cornelissen Paul Baas Vincent Van der Noort Jacobus A. Burgers Joachim G. Aerts |
| author_facet | Floris Dammeijer Cornedine J. De Gooijer Mandy van Gulijk Melanie Lukkes Larissa Klaase Lysanne A. Lievense Cynthia Waasdorp Merel Jebbink Gerben P. Bootsma Jos A. Stigt Bonne Biesma Margaretha E.H. Kaijen-Lambers Joanne Mankor Heleen Vroman Robin Cornelissen Paul Baas Vincent Van der Noort Jacobus A. Burgers Joachim G. Aerts |
| author_sort | Floris Dammeijer |
| collection | DOAJ |
| description | Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies. |
| first_indexed | 2024-12-16T07:17:05Z |
| format | Article |
| id | doaj.art-3c5ff16d06e342ff8c1730cb7bdef69d |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-16T07:17:05Z |
| publishDate | 2021-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-3c5ff16d06e342ff8c1730cb7bdef69d2022-12-21T22:39:44ZengElsevierEBioMedicine2352-39642021-02-0164103160Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical responseFloris Dammeijer0Cornedine J. De Gooijer1Mandy van Gulijk2Melanie Lukkes3Larissa Klaase4Lysanne A. Lievense5Cynthia Waasdorp6Merel Jebbink7Gerben P. Bootsma8Jos A. Stigt9Bonne Biesma10Margaretha E.H. Kaijen-Lambers11Joanne Mankor12Heleen Vroman13Robin Cornelissen14Paul Baas15Vincent Van der Noort16Jacobus A. Burgers17Joachim G. Aerts18Department of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; Corresponding authors.Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the NetherlandsDepartment of Pulmonary Medicine, Zuyderland Medical Centre, Heerlen, the NetherlandsDepartment of Pulmonary Medicine, Isala Hospital, Zwolle, the NetherlandsDepartment of Pulmonary Medicine, Jeroen Bosch Hospital, Den Bosch, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the NetherlandsDepartment of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the NetherlandsDepartment of Biometrics, Netherlands Cancer Institute Amsterdam, the NetherlandsDepartment of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam, the NetherlandsDepartment of Pulmonary Medicine, Erasmus MC Cancer Institute, Doctor Molewaterplein 40, 3015 GD Rotterdam, the Netherlands; Corresponding authors.Background: Gemcitabine is a frequently used chemotherapeutic agent but its effects on the immune system are incompletely understood. Recently, the randomized NVALT19-trial revealed that maintenance gemcitabine after first-line chemotherapy significantly prolonged progression-free survival (PFS) compared to best supportive care (BSC) in malignant mesothelioma. Whether these effects are paralleled by changes in circulating immune cell subsets is currently unknown. These analyses could offer improved mechanistic insights into the effects of gemcitabine on the host and guide development of effective combination therapies in mesothelioma. Methods: We stained peripheral blood mononuclear cells (PBMCs) and myeloid-derived suppressor cells (MDSCs) at baseline and 3 weeks following start of gemcitabine or BSC treatment in a subgroup of mesothelioma patients included in the NVALT19-trial. In total, 24 paired samples including both MDSCs and PBMCs were included. We performed multicolour flow-cytometry to assess co-inhibitory and-stimulatory receptor- and cytokine expression and matched these parameters with PFS and OS. Findings: Gemcitabine treatment was significantly associated with an increased NK-cell- and decreased T-regulatory cell proliferation whereas the opposite occurred in control patients. Furthermore, myeloid-derived suppressor cells (MDSCs) frequencies were lower in gemcitabine-treated patients and this correlated with increased T-cell proliferation following treatment. Whereas gemcitabine variably altered co-inhibitory receptor expression, co-stimulatory molecules including ICOS, CD28 and HLA-DR were uniformly increased across CD4+ T-helper, CD8+ T- and NK-cells. Although preliminary in nature, the increase in NK-cell proliferation and PD-1 expression in T cells following gemcitabine treatment was associated with improved PFS and OS. Interpretation: Gemcitabine treatment was associated with widespread effects on circulating immune cells of mesothelioma patients with responding patients displaying increased NK-cell and PD-1 + T-cell proliferation. These exploratory data provide a platform for future on treatment-biomarker development and novel combination treatment strategies.http://www.sciencedirect.com/science/article/pii/S2352396420305363Malignant mesotheliomaLymphocytesMyeloid-derived suppressor cellsGemcitabineImmunotherapy |
| spellingShingle | Floris Dammeijer Cornedine J. De Gooijer Mandy van Gulijk Melanie Lukkes Larissa Klaase Lysanne A. Lievense Cynthia Waasdorp Merel Jebbink Gerben P. Bootsma Jos A. Stigt Bonne Biesma Margaretha E.H. Kaijen-Lambers Joanne Mankor Heleen Vroman Robin Cornelissen Paul Baas Vincent Van der Noort Jacobus A. Burgers Joachim G. Aerts Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response EBioMedicine Malignant mesothelioma Lymphocytes Myeloid-derived suppressor cells Gemcitabine Immunotherapy |
| title | Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response |
| title_full | Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response |
| title_fullStr | Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response |
| title_full_unstemmed | Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response |
| title_short | Immune monitoring in mesothelioma patients identifies novel immune-modulatory functions of gemcitabine associating with clinical response |
| title_sort | immune monitoring in mesothelioma patients identifies novel immune modulatory functions of gemcitabine associating with clinical response |
| topic | Malignant mesothelioma Lymphocytes Myeloid-derived suppressor cells Gemcitabine Immunotherapy |
| url | http://www.sciencedirect.com/science/article/pii/S2352396420305363 |
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