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Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1

2022; Nature Portfolio; Volume: 3; Issue: 8 Linguagem: Inglês

10.1038/s43018-022-00405-x

2662-1347

Nathaniel W. Mabe, Min Huang, Guillermo Nicolás Dalton, Gabriela Alexe, Daniel A. Schaefer, Anna C. Geraghty, Amanda L. Robichaud, Amy Saur Conway, Delan Khalid, Marius Marc-Daniel Mader, Julia A. Belk, Kenneth N. Ross, Michal Sheffer, Miles H. Linde, Nghi Ly, Winnie Yao, Maria Caterina Rotiroti, Benjamin Smith, Marius Wernig, Carolyn R. Bertozzi, Michelle Monje, Constantine S. Mitsiades, Ravindra Majeti, Ansuman T. Satpathy, Kimberly Stegmaier, Robbie G. Majzner,

Ubiquitin and proteasome pathways

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. Mabe et al. find that GD2 levels correlate with lineage plasticity in neuroblastoma and identify ST8SIA1 as the key enzyme in GD2 synthesis. EZH2 inhibition in mesenchymal neuroblastoma cells elevates ST8SIA1, synergizing with anti-GD2 antibodies.