| Literature DB >> 35817829 |
Nathaniel W Mabe1,2, Min Huang3, Guillermo N Dalton3, Gabriela Alexe1,2, Daniel A Schaefer1, Anna C Geraghty4, Amanda L Robichaud1, Amy S Conway1, Delan Khalid1, Marius M Mader5,6, Julia A Belk7, Kenneth N Ross1,2, Michal Sheffer8, Miles H Linde9,10, Nghi Ly6, Winnie Yao6, Maria Caterina Rotiroti3, Benjamin A H Smith11, Marius Wernig5,6, Carolyn R Bertozzi12,13, Michelle Monje4,13, Constantine S Mitsiades8, Ravindra Majeti9, Ansuman T Satpathy6,14, Kimberly Stegmaier15,16, Robbie G Majzner17,18,19.
Abstract
Immunotherapy with anti-GD2 antibodies has advanced the treatment of children with high-risk neuroblastoma, but nearly half of patients relapse, and little is known about mechanisms of resistance to anti-GD2 therapy. Here, we show that reduced GD2 expression was significantly correlated with the mesenchymal cell state in neuroblastoma and that a forced adrenergic-to-mesenchymal transition (AMT) conferred downregulation of GD2 and resistance to anti-GD2 antibody. Mechanistically, low-GD2-expressing cell lines demonstrated significantly reduced expression of the ganglioside synthesis enzyme ST8SIA1 (GD3 synthase), resulting in a bottlenecking of GD2 synthesis. Pharmacologic inhibition of EZH2 resulted in epigenetic rewiring of mesenchymal neuroblastoma cells and re-expression of ST8SIA1, restoring surface expression of GD2 and sensitivity to anti-GD2 antibody. These data identify developmental lineage as a key determinant of sensitivity to anti-GD2 based immunotherapies and credential EZH2 inhibitors for clinical testing in combination with anti-GD2 antibody to enhance outcomes for children with neuroblastoma.Entities:
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Year: 2022 PMID： 35817829 DOI： 10.1038/s43018-022-00405-x
Source DB: PubMed Journal: Nat Cancer ISSN： 2662-1347