Dana-Farber Cancer Institute, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Leukemia. 2018 Mar;32(3):752-764. doi: 10.1038/leu.2017.316. Epub 2017 Nov 1.
X-box binding protein 1 (XBP1), CD138 (Syndecan-1) and CS1 (SLAMF7) are highly expressed antigens in cancers including multiple myeloma (MM). Here, we identify and characterize immunogenic HLA-A24 peptides derived from these antigens for potential vaccination therapy of HLA-A24+ patients with MM. The identified immunogenic HLA-A24-specific XBP1 unspliced (UN) (I S P W I L A V L), XBP1 spliced (SP) (V Y P E G P S S L), CD138 (I F A V C L V G F) and CS1 (L F V L G L F L W) peptides induced antigen-specific CTL with anti-MM activity in an HLA-A24 restricted manner. Furthermore, a cocktail containing the four HLA-A24 peptides evoked MM-specific CTL with distinct phenotypic profiles (CD28, CD40L, 41BB, CD38, CD69) and anti-tumor activities, evidenced by perforin upregulation, CD107a degranulation (cytotoxicity) and Th1-type cytokines (IFN-γ/IL-2/TNF-α) production in response to HLA-A24 MM cells. The multipeptide-specific CTL included antigen-specific memory CD8 T cells expressing both T-cell activation (CD38, CD69) and immune checkpoints antigens (CTLA, PD-1, LAG-3, TIM-3). These results provide the framework for a multipeptide vaccination therapy to induce tumor-specific CTL in HLA-A24-positive patients with myeloma and other cancers expressing these antigens.
X 盒结合蛋白 1（XBP1）、CD138（Syndecan-1）和 CS1（SLAMF7）是包括多发性骨髓瘤（MM）在内的多种癌症中高度表达的抗原。在这里，我们鉴定和表征了这些抗原来源的免疫原性 HLA-A24 肽，以用于 HLA-A24+MM 患者的潜在疫苗治疗。鉴定的免疫原性 HLA-A24 特异性 XBP1 未剪接（UN）（I S P W I L A V L）、XBP1 剪接（SP）（V Y P E G P S S L）、CD138（I F A V C L V G F）和 CS1（L F V L G L F L W）肽以 HLA-A24 限制的方式诱导具有抗 MM 活性的抗原特异性 CTL。此外，包含四种 HLA-A24 肽的鸡尾酒在 MM 特异性 CTL 中引起了不同表型特征（CD28、CD40L、41BB、CD38、CD69）和抗肿瘤活性，这表现在效应细胞中穿孔素上调、CD107a 脱颗粒（细胞毒性）和 Th1 型细胞因子（IFN-γ/IL-2/TNF-α）的产生。多肽特异性 CTL 包括表达 T 细胞激活（CD38、CD69）和免疫检查点抗原（CTLA、PD-1、LAG-3、TIM-3）的抗原特异性记忆 CD8 T 细胞。这些结果为 HLA-A24 阳性多发性骨髓瘤和其他表达这些抗原的癌症患者诱导肿瘤特异性 CTL 的多肽疫苗治疗提供了框架。
