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

当前位置： X-MOL 学术 › Nat. Cancer › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Transition to a mesenchymal state in neuroblastoma confers resistance to anti-GD2 antibody via reduced expression of ST8SIA1
Nature Cancer ( IF 23.5 ) Pub Date : 2022-07-11 , DOI: 10.1038/s43018-022-00405-x
Nathaniel W Mabe _{1,

2} , Min Huang ₃ , Guillermo N Dalton ₃ , Gabriela Alexe _{1,

2} , Daniel A Schaefer ₁ , Anna C Geraghty ₄ , Amanda L Robichaud ₁ , Amy S Conway ₁ , Delan Khalid ₁ , Marius M Mader _{5,

6} , Julia A Belk ₇ , Kenneth N Ross _{1,

2} , Michal Sheffer ₈ , Miles H Linde _{9,

10} , Nghi Ly ₆ , Winnie Yao ₆ , Maria Caterina Rotiroti ₃ , Benjamin A H Smith ₁₁ , Marius Wernig _{5,

6} , Carolyn R Bertozzi _{12,

13} , Michelle Monje _{4,

13} , Constantine S Mitsiades ₈ , Ravindra Majeti ₉ , Ansuman T Satpathy _{6,

14} , Kimberly Stegmaier _{1,

2} , Robbie G Majzner _{3,

15,

16}

Affiliation

Department of Pediatric Oncology, Dana-Farber Cancer Institute and Boston Children's Hospital, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA.
Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Computer Science, Stanford University School of Medicine, Stanford, CA, USA.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Department of Medicine, Division of Hematology, Stanford University School of Medicine, Stanford, CA, USA.
Immunology Graduate Program, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemical & Systems Biology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Chemistry, Stanford University School of Medicine, Stanford, CA, USA.
Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA.
Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA.

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.

中文翻译：

神经母细胞瘤向间充质状态的转变通过减少 ST8SIA1 的表达而赋予抗 GD2 抗体抗性

使用抗 GD2 抗体的免疫疗法已经推进了高危神经母细胞瘤儿童的治疗，但近一半的患者会复发，并且人们对抗 GD2 疗法的耐药机制知之甚少。在这里，我们表明，GD2 表达的减少与神经母细胞瘤中的间充质细胞状态显着相关，并且强制肾上腺素能向间充质转变（AMT）导致 GD2 下调和抗 GD2 抗体抵抗。从机制上讲，低 GD2 表达细胞系表现出神经节苷脂合成酶ST8SIA1 （GD3 合酶）的表达显着降低，导致 GD2 合成出现瓶颈。 EZH2 的药理学抑制导致间充质神经母细胞瘤细胞的表观遗传重新布线和ST8SIA1的重新表达，恢复 GD2 的表面表达和对抗 GD2 抗体的敏感性。这些数据表明，发育谱系是抗 GD2 免疫疗法和 EZH2 抑制剂敏感性的关键决定因素，EZH2 抑制剂与抗 GD2 抗体联合用于临床测试，可提高神经母细胞瘤儿童的预后。

更新日期：2022-07-12

点击分享查看原文

点击收藏

阅读更多本刊新发论文