Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma
Background Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myel...
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BMJ Publishing Group
2023-01-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/11/1/e005319.full |
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| author | Marie Törngren Rong Fan Eline Menu Helena Eriksson Karin Vanderkerken Andrew Chantry Hatice Satilmis Niels Vandewalle Emma Verheye Philip Vlummens Anke Maes Catharina Muylaert Elke De Bruyne Holly Evans Nathan De Beule Dirk Hose Ken Maes Karine Breckpot Kim De Veirman |
| author_facet | Marie Törngren Rong Fan Eline Menu Helena Eriksson Karin Vanderkerken Andrew Chantry Hatice Satilmis Niels Vandewalle Emma Verheye Philip Vlummens Anke Maes Catharina Muylaert Elke De Bruyne Holly Evans Nathan De Beule Dirk Hose Ken Maes Karine Breckpot Kim De Veirman |
| author_sort | Marie Törngren |
| collection | DOAJ |
| description | Background Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment.Methods We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models.Results Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo.Conclusion Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients. |
| format | Article |
| id | doaj-art-d2125622a63f49eba73f4bc280a4cd85 |
| institution | Kabale University |
| issn | 2051-1426 |
| language | English |
| publishDate | 2023-01-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d2125622a63f49eba73f4bc280a4cd852025-02-03T11:55:09ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262023-01-0111110.1136/jitc-2022-005319Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myelomaMarie Törngren0Rong Fan1Eline Menu2Helena Eriksson3Karin Vanderkerken4Andrew Chantry5Hatice Satilmis6Niels Vandewalle7Emma Verheye8Philip Vlummens9Anke Maes10Catharina Muylaert11Elke De Bruyne12Holly Evans13Nathan De Beule14Dirk Hose15Ken Maes16Karine Breckpot17Kim De Veirman18Active Biotech AB, Lund, SwedenprofessorLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumActive Biotech AB, Lund, SwedenLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumDepartment of Oncology and Metabolism, Sheffield Myeloma Research Team, University of Sheffield, Sheffield, UKLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumLab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumDepartment of Oncology and Metabolism, Sheffield Myeloma Research Team, University of Sheffield, Sheffield, UKDepartment of Clinical Hematology, Universitair Ziekenhuis Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumCenter for Medical Genetics, Vrije Universiteit Brussel (VUB), Universitair Ziekenhuis Brussel (UZ Brussel), Brussels, BelgiumTranslational Oncology Research Center (TORC), Department of Biomedical Sciences, Laboratory for Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, Brussels, BelgiumLaboratory for Hematology and Immunology, Department of Biomedical Sciences, Vrije Universiteit Brussel, Brussels, BelgiumBackground Immunotherapy emerged as a promising treatment option for multiple myeloma (MM) patients. However, therapeutic efficacy can be hampered by the presence of an immunosuppressive bone marrow microenvironment including myeloid cells. S100A9 was previously identified as a key regulator of myeloid cell accumulation and suppressive activity. Tasquinimod, a small molecule inhibitor of S100A9, is currently in a phase Ib/IIa clinical trial in MM patients (NCT04405167). We aimed to gain more insights into its mechanisms of action both on the myeloma cells and the immune microenvironment.Methods We analyzed the effects of tasquinimod on MM cell viability, cell proliferation and downstream signaling pathways in vitro using RNA sequencing, real-time PCR, western blot analysis and multiparameter flow cytometry. Myeloid cells and T cells were cocultured at different ratios to assess tasquinimod-mediated immunomodulatory effects. The in vivo impact on immune cells (myeloid cell subsets, macrophages, dendritic cells), tumor load, survival and bone disease were elucidated using immunocompetent 5TMM models.Results Tasquinimod treatment significantly decreased myeloma cell proliferation and colony formation in vitro, associated with an inhibition of c-MYC and increased p27 expression. Tasquinimod-mediated targeting of the myeloid cell population resulted in increased T cell proliferation and functionality in vitro. Notably, short-term tasquinimod therapy of 5TMM mice significantly increased the total CD11b+ cells and shifted this population toward a more immunostimulatory state, which resulted in less myeloid-mediated immunosuppression and increased T cell activation ex vivo. Tasquinimod significantly reduced the tumor load and increased the trabecular bone volume, which resulted in prolonged overall survival of MM-bearing mice in vivo.Conclusion Our study provides novel insights in the dual therapeutic effects of the immunomodulator tasquinimod and fosters its evaluation in combination therapy trials for MM patients.https://jitc.bmj.com/content/11/1/e005319.full |
| spellingShingle | Marie Törngren Rong Fan Eline Menu Helena Eriksson Karin Vanderkerken Andrew Chantry Hatice Satilmis Niels Vandewalle Emma Verheye Philip Vlummens Anke Maes Catharina Muylaert Elke De Bruyne Holly Evans Nathan De Beule Dirk Hose Ken Maes Karine Breckpot Kim De Veirman Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma Journal for ImmunoTherapy of Cancer |
| title | Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma |
| title_full | Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma |
| title_fullStr | Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma |
| title_full_unstemmed | Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma |
| title_short | Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma |
| title_sort | tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c myc expression in multiple myeloma |
| url | https://jitc.bmj.com/content/11/1/e005319.full |
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