Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma.,Blood Cancer Journal

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Mass spectrometry-based identification of a B-cell maturation antigen-derived T-cell epitope for antigen-specific immunotherapy of multiple myeloma.
Blood Cancer Journal ( IF 12.9 ) Pub Date : 2020-02-28 , DOI: 10.1038/s41408-020-0288-3
Tatjana Bilich _{1,

2} , Annika Nelde _{1,

2} , Jens Bauer _{1,

2} , Simon Walz _{2,

3} , Malte Roerden ₄ , Helmut R Salih ₁ , Katja Weisel _{4,

5} , Britta Besemer ₄ , Ana Marcu ₂ , Maren Lübke ₂ , Juliane Schuhmacher ₂ , Marian C Neidert ₆ , Hans-Georg Rammensee _{2,

7} , Stefan Stevanović _{2,

7} , Juliane S Walz ₁

Affiliation

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.

中文翻译：

基于质谱法鉴定 B 细胞成熟抗原衍生的 T 细胞表位，用于多发性骨髓瘤的抗原特异性免疫治疗。

B 细胞成熟抗原 (BCMA) 目前正在被评估为有前途的肿瘤相关表面抗原，用于多发性骨髓瘤 (MM) 中基于 T 细胞的免疫治疗方法，例如 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来自 BCMA 细胞内结构域的 HLA 呈递抗原。通过分析原代 MM 样品和 MM 细胞系的质谱获得的免疫肽组数据集的 BCMA 衍生 HLA 配体，我们鉴定了天然存在的 HLA-B*18 限制性配体 P(BCMA)B*18。此外，在初级 CLL 样本中鉴定出了 P(BCMA)B*18，从而扩大了可能的应用范围。P(BCMA)B*18 从健康志愿者的幼稚 CD8+ T 细胞中诱导出多功能 BCMA 特异性细胞。这些 T 细胞表现出自体肽负载细胞的抗原特异性裂解。即使在 MM 的免疫抑制背景下，我们也检测到患者中针对 P(BCMA)B*18 的自发记忆 T 细胞反应。通过在体外应用 CTLA-4 和 PD-1 抑制，我们在缺乏预先存在的 BCMA 定向免疫反应的 MM 患者中诱导了多功能 P(BCMA)B*18 特异性 CD8+ T 细胞。最后，我们可以使用患者来源的 P(BCMA)B*18 特异性 T 细胞来显示自体肽负载靶细胞甚至自然呈递 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 细胞表位代表了基于 T 细胞的免疫治疗和 B 细胞恶性肿瘤患者免疫治疗后监测的有希望的靶标。

更新日期：2020-02-28

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