文章：

基于质谱鉴定的B细胞成熟抗原衍生T细胞表位用于多发性骨髓瘤的抗原特异性免疫治疗

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma

原文发布日期：2020-02-28

DOI: 10.1038/s41408-020-0288-3

类型: Article

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英文摘要：

The B-cell maturation antigen (BCMA) is currently being evaluated as promising tumor-associated surface antigen for T-cell-based immunotherapy approaches, such as CAR T cells and bispecific antibodies, in multiple myeloma (MM). Cytotoxic T cells bearing BCMA-specific T-cell receptors might further allow targeting HLA-presented antigens derived from the intracellular domain of BCMA. By analyzing a mass spectrometry-acquired immunopeptidome dataset of primary MM samples and MM cell lines for BCMA-derived HLA ligands, we identified the naturally presented HLA-B*18-restricted ligand P(BCMA)B*18. Additionally, P(BCMA)B*18 was identified on primary CLL samples, thereby expanding the range for possible applications. P(BCMA)B*18 induced multifunctional BCMA-specific cells de novo from naïve CD8+ T cells of healthy volunteers. These T cells exhibited antigen-specific lysis of autologous peptide-loaded cells. Even in the immunosuppressive context of MM, we detected spontaneous memory T-cell responses against P(BCMA)B*18 in patients. By applying CTLA-4 and PD-1 inhibition in vitro we induced multifunctional P(BCMA)B*18-specific CD8+ T cells in MM patients lacking preexisting BCMA-directed immune responses. Finally, we could show antigen-specific lysis of autologous peptide-loaded target cells and even MM.1S cells naturally presenting P(BCMA)B*18 using patient-derived P(BCMA)B*18-specific T cells. Hence, this BCMA-derived T-cell epitope represents a promising target for T-cell-based immunotherapy and monitoring following immunotherapy in B-cell malignancy patients.
 

摘要翻译： 

B细胞成熟抗原（BCMA）目前被认为是一种有前景的肿瘤相关表面抗原，正被评估用于多发性骨髓瘤（MM）中基于T细胞的免疫治疗策略，如CAR T细胞和双特异性抗体。携带BCMA特异性T细胞受体的细胞毒性T细胞可能进一步靶向源自BCMA胞内结构域的HLA呈递抗原。通过分析原发性MM样本和MM细胞系的质谱获取的免疫肽组数据，以寻找BCMA衍生的HLA配体，我们鉴定出天然呈递的HLA-B*18限制性配体P(BCMA)B*18。此外，在原发性CLL样本中也鉴定出P(BCMA)B*18，从而扩展了其潜在应用范围。P(BCMA)B*18能够从健康志愿者的初始CD8+ T细胞中从头诱导多功能BCMA特异性细胞。这些T细胞对负载自体肽的细胞表现出抗原特异性裂解作用。即使在MM的免疫抑制环境中，我们也在患者中检测到针对P(BCMA)B*18的自发性记忆T细胞应答。通过体外应用CTLA-4和PD-1抑制，我们在缺乏预先存在的BCMA定向免疫应答的MM患者中诱导了多功能P(BCMA)B*18特异性CD8+ T细胞。最后，我们利用患者来源的P(BCMA)B*18特异性T细胞，证实了其对负载自体肽的靶细胞乃至天然呈递P(BCMA)B*18的MM.1S细胞的抗原特异性裂解。因此，这种BCMA衍生的T细胞表位为B细胞恶性肿瘤患者基于T细胞的免疫治疗及治疗后监测提供了一个有前景的靶点。

原文链接：

Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma