Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA.
Division of Surgical Oncology, Department of Surgery, Emory University, Atlanta, GA, USA.
Oncoimmunology. 2023 Aug 5;12(1):2240678. doi: 10.1080/2162402X.2023.2240678. eCollection 2023.
Pediatric patients with high-risk neuroblastoma often relapse with chemotherapy-resistant, incurable disease. Relapsed neuroblastomas harbor chemo-resistant mesenchymal tumor cells and increased expression/activity of the transcriptional co-regulator, the Yes-Associated Protein (YAP). Patients with relapsed neuroblastoma are often treated with immunotherapy such as the anti-GD2 antibody, dinutuximab, in combination with chemotherapy. We have previously shown that YAP mediates both chemotherapy and MEK inhibitor resistance in relapsed mutated neuroblastoma and so posited that YAP might also be involved in anti-GD2 antibody resistance. We now show that YAP genetic inhibition significantly enhances sensitivity of mesenchymal neuroblastomas to dinutuximab and gamma delta (γδ) T cells both and . Mechanistically, YAP inhibition induces increased GD2 cell surface expression through upregulation of , the gene encoding GD3 synthase and the rate-limiting enzyme in GD2 biosynthesis. The mechanism of suppression by YAP is independent of expression, a mesenchymal master transcription factor, suggesting YAP may be the downstream effector of mesenchymal GD2 resistance. These results therefore identify YAP as a therapeutic target to augment GD2 immunotherapy responses in patients with neuroblastoma.
患有高危神经母细胞瘤的儿科患者常因化疗耐药、无法治愈的疾病而复发。复发的神经母细胞瘤含有化疗耐药的间充质肿瘤细胞，并增加转录共调节剂 Yes 相关蛋白 (YAP) 的表达/活性。复发神经母细胞瘤患者常接受免疫治疗，如抗 GD2 抗体、dinutuximab，与化疗联合使用。我们之前已经表明，YAP 在复发的突变神经母细胞瘤中既介导化疗耐药，也介导 MEK 抑制剂耐药，因此我们推测 YAP 也可能参与抗 GD2 抗体耐药。我们现在表明，YAP 的遗传抑制显著增强了间充质神经母细胞瘤对 dinutuximab 和 γδ (γδ) T 细胞的敏感性。机制上，YAP 抑制通过上调编码 GD3 合酶和 GD2 生物合成限速酶的基因，诱导 GD2 细胞表面表达增加。YAP 抑制的机制独立于间充质主转录因子表达，这表明 YAP 可能是间充质 GD2 耐药的下游效应因子。因此，这些结果确定 YAP 为一种治疗靶点，可增强神经母细胞瘤患者的 GD2 免疫治疗反应。
