دورية أكاديمية

Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma

التفاصيل البيبلوغرافية
العنوان: Tasquinimod suppresses tumor cell growth and bone resorption by targeting immunosuppressive myeloid cells and inhibiting c-MYC expression in multiple myeloma
المؤلفون: 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
المصدر: Journal for ImmunoTherapy of Cancer, Vol 11, Iss 1 (2023)
بيانات النشر: BMJ Publishing Group, 2023.
سنة النشر: 2023
المجموعة: LCC:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
مصطلحات موضوعية: Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
الوصف: 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.
نوع الوثيقة: article
وصف الملف: electronic resource
اللغة: English
تدمد: 2051-1426
Relation: https://jitc.bmj.com/content/11/1/e005319.full; https://doaj.org/toc/2051-1426
DOI: 10.1136/jitc-2022-005319
URL الوصول: https://doaj.org/article/d2125622a63f49eba73f4bc280a4cd85
رقم الأكسشن: edsdoj.2125622a63f49eba73f4bc280a4cd85
قاعدة البيانات: Directory of Open Access Journals
الوصف
تدمد:20511426
DOI:10.1136/jitc-2022-005319