由于缺乏高度癌症特异性的表面标志物，安全地扩大细胞疗法的适应症一直具有挑战性。在这里，我们探讨了这样的假设：肿瘤细胞表达癌症特异性表面蛋白构象，这些构象对于评估基因或蛋白质表达的标准靶标发现流程来说是不可见的，并且这些构象可以被识别并进行免疫治疗靶向。我们将这种将交联质谱与糖蛋白表面捕获相结合的策略称为“结构表面组学”。作为原理证明，我们将该技术应用于急性髓系白血病 (AML)，这是一种血液恶性肿瘤，其结果令人沮丧，并且没有已知的最佳免疫治疗靶点。我们将整合素 β2 的激活构象确定为结构明确、广泛表达的 AML 特异性靶标。我们开发并表征了针对这种蛋白质构象的重组抗体，并表明嵌合抗原受体 T 细胞消除了 AML 细胞和患者来源的异种移植物，而对正常造血细胞没有明显的毒性。我们的研究结果验证了 AML 构象特异性靶抗原，并展示了更广泛地应用这些策略的工具包。© 2023。作者。

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin β2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.© 2023. The Author(s).