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

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

doi:10.1038/s43018-022-00405-x

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

Nat Cancer. 2022 Aug;3(8):976-993. doi: 10.1038/s43018-022-00405-x. Epub 2022 Jul 11.

Authors

Nathaniel W Mabe^#^{1

2}, Min Huang^#³, Guillermo N Dalton³, Gabriela Alexe^{1

2}, Daniel A Schaefer¹, Anna C Geraghty⁴, Amanda L Robichaud¹, Amy S Conway¹, Delan Khalid¹, Marius M Mader^{5

6}, Julia A Belk⁷, Kenneth N Ross^{1

2}, Michal Sheffer⁸, Miles H Linde^{9

10}, Nghi Ly⁶, Winnie Yao⁶, Maria Caterina Rotiroti³, Benjamin A H Smith¹¹, Marius Wernig^{5

6}, Carolyn R Bertozzi^{12

13}, Michelle Monje^{4

13}, Constantine S Mitsiades⁸, Ravindra Majeti⁹, Ansuman T Satpathy^{6

14}, Kimberly Stegmaier^{15

16}, Robbie G Majzner^{17

18

19}

Affiliations

¹ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
⁴ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
⁵ Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.
⁶ Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
⁷ Department of Computer Science, Stanford University School of Medicine, Stanford, CA, USA.
⁸ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
¹⁰ Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
¹¹ Department of Chemical & Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
¹² Department of Chemistry, Stanford University School of Medicine, Stanford, CA, USA.
¹³ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
¹⁴ Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
¹⁵ Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA. Kimberly_stegmaier@dfci.harvard.edu.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA. Kimberly_stegmaier@dfci.harvard.edu.
¹⁷ Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA. rmajzner@stanford.edu.
¹⁸ Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA. rmajzner@stanford.edu.
¹⁹ Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. rmajzner@stanford.edu.

^# Contributed equally.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Antibodies, Monoclonal
Child
Gangliosides*
Humans
Immunotherapy
Neoplasm Recurrence, Local / chemically induced
Neuroblastoma* / drug therapy

Substances

Antibodies, Monoclonal
Gangliosides

Abstract

Publication types

MeSH terms

Substances

Grants and funding