神经母细胞瘤是一种异质性疾病，具有由不同转录因子网络驱动的肾上腺素能 (ADRN) 和治疗耐药性间充质 (MES) 样细胞。在这里，我们研究了每种神经母细胞瘤亚型中免疫治疗靶标的表达，并提出了泛神经母细胞瘤和细胞状态特异性可靶向细胞表面蛋白。我们将细胞系、患者来源的异种移植物和患者样本表征为 ADRN 主导或 MES 主导，以定义亚型特异性和泛神经母细胞瘤基因集。通过 ChIP 测序、免疫印迹和流式细胞术在神经母细胞瘤细胞系和同基因 ADRN 至 MES 过渡细胞系模型中验证靶标。最后，我们评估了 MES 特异性药物的体内和体外活性。大多数针对神经母细胞瘤开发的免疫治疗靶点在 ADRN 亚型中表现出显着较高的表达，而在 MES 样肿瘤细胞中表达有限。相比之下，CD276 (B7-H3) 和 L1CAM 在 ADRN 和 MES 状态下均保持表达。我们鉴定了在 MES 主导的样品中富集的几种受体酪氨酸激酶 (RTK)，并表明 ADCT-601 靶向的 AXL 在 MES 主导的细胞系中具有有效的细胞毒性，并在 MES 细胞系衍生的异种移植物中显示出特异性的抗肿瘤活性。神经母细胞瘤的策略必须解决抗原密度表观遗传下调作为免疫逃避机制的潜力。我们确定了几种 RTK 作为候选 MES 特异性免疫治疗靶蛋白，用于消除治疗耐药细胞。我们假设，当靶向泛神经母细胞瘤细胞表面蛋白（如 B7-H3 和 L1CAM）和/或同时考虑 ADRN 和 MES 细胞状态的双重靶向策略时，免疫逃逸现象不太可能发生。丰富的免疫治疗靶点。亚型特异性靶点可能容易受到表观遗传介导的下调的影响。发育中的免疫治疗靶点 B7-H3 和 L1CAM 显示“泛亚型”表达。神经母细胞瘤是一种致命的儿童恶性肿瘤，表现出细胞可塑性抗癌疗法。几种质膜蛋白正在被开发作为这种疾病的免疫治疗靶点。在这里，我们定义了哪些细胞表面蛋白在肾上腺素能细胞状态转换期间容易受到表观遗传调节的下调，并提出了免疫治疗策略来预测和规避获得性免疫治疗耐药性。

Neuroblastoma is a heterogeneous disease with adrenergic (ADRN)- and therapy resistant mesenchymal (MES)-like cells driven by distinct transcription factor networks. Here, we investigate the expression of immunotherapeutic targets in each neuroblastoma subtype and propose pan-neuroblastoma and cell state specific targetable cell-surface proteins.We characterized cell lines, patient-derived xenografts, and patient samples as ADRN-dominant or MES- dominant to define subtype-specific and pan-neuroblastoma gene sets. Targets were validated with ChIP- sequencing, immunoblotting, and flow cytometry in neuroblastoma cell lines and isogenic ADRN-to-MES transition cell line models. Finally, we evaluated the activity of MES-specific agents in vivo and in vitro .Most immunotherapeutic targets being developed for neuroblastoma showed significantly higher expression in the ADRN subtype with limited expression in MES-like tumor cells. In contrast, CD276 (B7-H3) and L1CAM maintained expression across both ADRN and MES states. We identified several receptor tyrosine kinases (RTKs) enriched in MES-dominant samples and showed that AXL targeting with ADCT-601 was potently cytotoxic in MES-dominant cell lines and showed specific anti-tumor activity in a MES cell line-derived xenograft.Immunotherapeutic strategies for neuroblastoma must address the potential of epigenetic downregulation of antigen density as a mechanism for immune evasion. We identified several RTKs as candidate MES-specific immunotherapeutic target proteins for the elimination of therapy-resistant cells. We hypothesize that the phenomena of immune escape will be less likely when targeting pan-neuroblastoma cell surface proteins such as B7-H3 and L1CAM, and/or dual targeting strategies that consider both the ADRN- and MES-cell states.Cellular plasticity influences the abundance of immunotherapeutic targets.Subtype-specific targets may be susceptible to epigenetically-mediated downregulation.Immunotherapeutic targets in development, B7-H3 and L1CAM, show "pan-subtype" expression.Neuroblastoma is a lethal childhood malignancy that shows cellular plasticity in response to anti-cancer therapies. Several plasma membrane proteins are being developed as immunotherapeutic targets in this disease. Here we define which cell surface proteins are susceptible to epigenetically regulated downregulation during an adrenergic to mesenchymal cell state switch and propose immunotherapeutic strategies to anticipate and circumvent acquired immunotherapeutic resistance.