FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W3101587777> ?p ?o ?g. }

• W3101587777 abstract "Background Myeloid-derived suppressor cells (MDSCs) accumulate in the blood and tumor microenvironment (TME) and suppress anti-tumor immune responses. 1 Cancer cells express the granulocyte-macrophage colony-stimulating factor (GM-CSF), which drives MDSC differentiation and function. 2 3 4 It is upregulated in several cancers, including mesothelioma, pancreatic and colorectal, and it is linked to higher levels of intra-tumoral MDSCs and poorer overall survival. 2 4 5 In animal models, knockdown of GM-CSF in pancreatic epithelium or pancreatic mesenchymal stem cells inhibits tumorigenesis, reduces intra-tumor MDSCs and enhances CD8+ T cell accumulation. 6 7 8 Therefore, targeting the GM-CSF receptor alpha (GM-CSFRα) on MDSCs is an attractive strategy to restore anti-tumor immunity. Mavrilimumab is a clinical stage fully human monoclonal antibody that blocks GM-CSFRα. It has demonstrated efficacy and acceptable safety profile in patients with rheumatoid arthritis, and it’s currently undergoing investigation in phase II studies in giant cell arteritis and in patients with severe COVID-19 pneumonia and hyper-inflammation ( NCT03827018 , NCT04397497 , respectively). The present study investigates its potential as a therapeutic strategy to target MDSCs in the TME as an adjuvant to immunotherapy. Methods Cancer cell supernatants were collected when cells reached confluency. Human GM-CSF was measured by ELISA. Healthy donor CD14+ monocytes were incubated (± mavrilimumab) with cancer cell supernatants for either 3 or 6 days followed by phenotypic analysis (CD14, CD33, HLA-DR, CD11b, CD206, CD80, PD-L1, Arginase-1) by flow cytometry. On day 3, autologous CD3+ T cells were stimulated with CD3/CD28 and IL-2 and co-cultured with putative MDSCs for 5 days. T-cell proliferation was evaluated by measuring carboxyfluorescein succinimidyl ester (CFSE) dilution in CD4+ and CD8+ T cells by flow cytometry. Results GM-CSF is expressed in the supernatant of cancer cell lines (HCT116, SW-480, Panc-1, Capan-1). Human monocytes cultured with conditioned medium from colorectal carcinoma (SW-480) or pancreatic adenocarcinoma (Capan-1) show downregulation of HLA-DR, increased expression of PD-L1, Arg-1, CD206, and can suppress T-cell proliferation in-vitro. Similarly, peripheral blood monocytes purified from pancreatic cancer patients suppress T-cell proliferation ex-vivo. Notably, Mavrilimumab inhibits the polarization of healthy donor monocytes to M-MDSCs and restores T-cell proliferation. Conclusions Targeting of GM-CSFRα with mavrilimumab may alleviate the pro-tumorigenic and immunosuppressive functions of MDSCs in the TME. Future clinical studies should evaluate whether targeting of the GM-CSFRα in combination with immune checkpoint inhibitors is a viable therapeutic option to bolster their efficacy. Ethics Approval The study was approved by the Institute of Immunology and Immunotherapy, University of Birmingham, UK Ethics Board. Healthy volunteer human material was obtained from commercial sources and approved by Stemexpress Institutional Review Board (IRB). References Law AMK, Valdes-Mora F, Gallego-Ortega D. Myeloid-Derived Suppressor Cells as a Therapeutic Target for Cancer. Cells 2020;9(3):561. Khanna S, Graef S, Mussai F, et al. Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients. Clin Cancer Res 2018;24(12):2859–2872. Dolcetti L, Peranzoni E, Ugel S, et al. Hierarchy of immunosuppressive strength among myeloid-derived suppressor cell subsets is determined by GM-CSF. Eur J Immunol 2010;40(1):22–35. Takeuchi S, Baghdadi M, Tsuchikawa T, et al. Chemotherapy-derived inflammatory responses accelerate the formation of immunosuppressive myeloid cells in the tissue microenvironment of human pancreatic cancer. Cancer Res 2015;75(13):2629–2640. Chen Y, Zhao Z, Chen Y, et al. An epithelial-to-mesenchymal transition-inducing potential of granulocyte macrophage colony-stimulating factor in colon cancer. Sci Rep 2017;7(1):8265. Bayne LJ, Beatty GL, Jhala N, et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 2012;21(6):822–835. Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell 2012;21(6):836–847. Waghray M, Yalamanchili M, Dziubinski M, et al. GM-CSF mediates mesenchymal-epithelial cross-talk in pancreatic cancer. Cancer Discov 2016;6(8):886–899." @default.
• W3101587777 created "2020-11-23" @default.
• W3101587777 creator A5006698523 @default.
• W3101587777 creator A5022301461 @default.
• W3101587777 creator A5052506270 @default.
• W3101587777 creator A5060426399 @default.
• W3101587777 creator A5074865959 @default.
• W3101587777 creator A5088695944 @default.
• W3101587777 creator A5031788917 @default.
• W3101587777 date "2020-11-01" @default.
• W3101587777 modified "2023-10-15" @default.
• W3101587777 title "473 Mavrilimumab, a human monoclonal antibody targeting GM-CSFRα, inhibits polarization to myeloid-derived suppressor cells (MDSCs) that express PD-L1 and restores T-cell proliferation in vitro" @default.
• W3101587777 doi "https://doi.org/10.1136/jitc-2020-sitc2020.0473" @default.
• W3101587777 hasPublicationYear "2020" @default.
• W3101587777 type Work @default.
• W3101587777 sameAs 3101587777 @default.
• W3101587777 citedByCount "1" @default.
• W3101587777 countsByYear W31015877772022 @default.
• W3101587777 crossrefType "journal-article" @default.
• W3101587777 hasAuthorship W3101587777A5006698523 @default.
• W3101587777 hasAuthorship W3101587777A5022301461 @default.
• W3101587777 hasAuthorship W3101587777A5031788917 @default.
• W3101587777 hasAuthorship W3101587777A5052506270 @default.
• W3101587777 hasAuthorship W3101587777A5060426399 @default.
• W3101587777 hasAuthorship W3101587777A5074865959 @default.
• W3101587777 hasAuthorship W3101587777A5088695944 @default.
• W3101587777 hasConcept C121608353 @default.
• W3101587777 hasConcept C126322002 @default.
• W3101587777 hasConcept C179185449 @default.
• W3101587777 hasConcept C203014093 @default.
• W3101587777 hasConcept C2776090121 @default.
• W3101587777 hasConcept C2776107976 @default.
• W3101587777 hasConcept C2777701055 @default.
• W3101587777 hasConcept C2780210213 @default.
• W3101587777 hasConcept C502942594 @default.
• W3101587777 hasConcept C55721878 @default.
• W3101587777 hasConcept C71924100 @default.
• W3101587777 hasConcept C79484868 @default.
• W3101587777 hasConcept C8891405 @default.
• W3101587777 hasConceptScore W3101587777C121608353 @default.
• W3101587777 hasConceptScore W3101587777C126322002 @default.
• W3101587777 hasConceptScore W3101587777C179185449 @default.
• W3101587777 hasConceptScore W3101587777C203014093 @default.
• W3101587777 hasConceptScore W3101587777C2776090121 @default.
• W3101587777 hasConceptScore W3101587777C2776107976 @default.
• W3101587777 hasConceptScore W3101587777C2777701055 @default.
• W3101587777 hasConceptScore W3101587777C2780210213 @default.
• W3101587777 hasConceptScore W3101587777C502942594 @default.
• W3101587777 hasConceptScore W3101587777C55721878 @default.
• W3101587777 hasConceptScore W3101587777C71924100 @default.
• W3101587777 hasConceptScore W3101587777C79484868 @default.
• W3101587777 hasConceptScore W3101587777C8891405 @default.
• W3101587777 hasLocation W31015877771 @default.
• W3101587777 hasOpenAccess W3101587777 @default.
• W3101587777 hasPrimaryLocation W31015877771 @default.
• W3101587777 hasRelatedWork W11055546 @default.
• W3101587777 hasRelatedWork W16473764 @default.
• W3101587777 hasRelatedWork W19818330 @default.
• W3101587777 hasRelatedWork W20203410 @default.
• W3101587777 hasRelatedWork W2151330 @default.
• W3101587777 hasRelatedWork W2773312 @default.
• W3101587777 hasRelatedWork W3959955 @default.
• W3101587777 hasRelatedWork W5668654 @default.
• W3101587777 hasRelatedWork W5924046 @default.
• W3101587777 hasRelatedWork W7677563 @default.
• W3101587777 isParatext "false" @default.
• W3101587777 isRetracted "false" @default.
• W3101587777 magId "3101587777" @default.
• W3101587777 workType "article" @default.