针对胰腺导管腺癌中质谱鉴定的天然表位的工程 TCR T 细胞疗法。
Engineered TCR T-cell therapy targeting mass spectrometry-identified natural epitope in PDAC.
机构信息
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA.
出版信息
Cancer Lett. 2023 Oct 1;573:216366. doi: 10.1016/j.canlet.2023.216366. Epub 2023 Aug 26.
Tumor antigens are crucial targets for T-cell-based therapy to induce tumor-specific rejection. However, identifying pancreatic ductal adenocarcinoma (PDAC)-specific T-cell epitopes has been challenging. Using advanced mass spectrometry (MS) analysis, we previously identified cancer-associated, class I MHC-bound epitopes shared by multiple PDAC patients with different HLA-A types. Here, we investigated one of these epitopes, LAMC2, a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2 peptide, we cloned T-cell receptors (TCRs) and transduced them into the Jurkat human T-cell line using a lentiviral vector. We found that Jurkat cells expressing LAMC2-specific TCRs resulted in potent, LAMC2 specific, in vitro cytotoxic effects on PDAC cells. Furthermore, in mice that harbored either subcutaneously or orthotopically implanted tumors originating from both HLA-A allele-matched and unmatched PDAC patients, tumor growth was suppressed in a LAMC2-dependent manner following the infusion of LAMC2-targeting T cells. We have therefore developed a LAMC2-specific TCR-based T-cell therapy strategy likely suitable for many PDAC patients. This is the first study to adopt MS analysis to identify natural CD8 T-cell epitopes in PDAC that could potentially serve as targets for PDAC immunotherapy.
肿瘤抗原是基于 T 细胞的治疗诱导肿瘤特异性排斥的关键靶标。然而，鉴定胰腺导管腺癌 (PDAC) 特异性 T 细胞表位一直具有挑战性。我们之前使用先进的质谱 (MS) 分析方法鉴定了多个具有不同 HLA-A 类型的 PDAC 患者共有的与癌症相关的、I 类 MHC 结合的表位。在这里，我们研究了这些表位之一，LAMC2，一种 LAMC2 蛋白上天然存在的非突变表位。在用 LAMC2 肽刺激后，我们使用慢病毒载体克隆了 T 细胞受体 (TCRs) 并将其转导到 Jurkat 人 T 细胞系中。我们发现表达 LAMC2 特异性 TCR 的 Jurkat 细胞在体外对 PDAC 细胞产生了强烈的、针对 LAMC2 的细胞毒性作用。此外，在皮下或原位植入源自 HLA-A 等位基因匹配和不匹配 PDAC 患者的肿瘤的小鼠中，在输注靶向 LAMC2 的 T 细胞后，肿瘤生长以 LAMC2 依赖的方式受到抑制。因此，我们已经开发了一种基于 LAMC2 特异性 TCR 的 T 细胞治疗策略，可能适合许多 PDAC 患者。这是第一项采用 MS 分析鉴定 PDAC 中天然 CD8 T 细胞表位的研究，这些表位可能成为 PDAC 免疫治疗的靶点。
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