靶向胰腺导管腺癌中质谱鉴定天然表位的工程化 TCR-T 细胞疗法

← 返回前沿论文

靶向胰腺导管腺癌中质谱鉴定天然表位的工程化 TCR-T 细胞疗法

英文原题：Engineered TCR T-cell therapy targeting mass spectrometry-identified natural epitope in PDAC.

查看英文原题

Engineered TCR T-cell therapy targeting mass spectrometry-identified natural epitope in PDAC.

PubMed 2023/08/26（内容时间） Cancer Lett Q1 · IF 11.8（JCR 2025）

技术：TCR-T 胰腺癌地区：美国

登录后收藏与关注全文解读加入对比

研究概要

肿瘤抗原是 T 细胞疗法诱导肿瘤特异性排斥反应的关键靶点。

中文摘要

肿瘤抗原是基于 T 细胞疗法诱导肿瘤特异性排斥反应的关键靶点，但鉴定胰腺导管腺癌（PDAC）特异性 T 细胞表位一直具有挑战性。我们此前利用先进质谱（MS）分析，鉴定出与癌症相关、由 I 类 MHC 分子结合、且在 HLA-A 类型不同的多名 PDAC 患者中共有的表位。本研究考察其中一种表位：LAMC2 203–211，它是 LAMC2 蛋白上天然存在、未经突变的表位。用 LAMC2 203–211 肽刺激后，研究人员克隆了 T 细胞受体（TCR），并通过慢病毒载体将其转导至人 Jurkat T 细胞系。表达 LAMC2 203–211 特异性 TCR 的 Jurkat 细胞可在体外对 PDAC 细胞产生强效且特异于 LAMC2 的细胞毒作用。此外，在皮下或原位植入来源于 HLA-A 等位基因匹配和不匹配 PDAC 患者肿瘤的小鼠中，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，我们开发了一种 LAMC2 特异性 TCR T 细胞治疗策略，可能适用于许多 PDAC 患者。据我们所知，这是首项采用 MS 分析鉴定 PDAC 中天然 CD8⁺ T 细胞表位、并提出其作为 PDAC 免疫治疗潜在靶点的研究。

展开英文摘要原文

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 203-211 , a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2 203-211 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 203-211 -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.

论文信息

作者: Wang J、Zhang T、Li P、Gai J、Chen S、Espinoza G、Kung HC、Zhang R
第一作者单位: 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.United States
通讯作者单位: 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; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, 21287, USA. Electronic address: lzheng6@jhmi.edu.United States
文献类型: 美国 NIH 资助研究 · 非美国政府资助研究
期刊: Cancer letters2023 Oct 1

原文标识: PubMed 37640197　·　DOI 10.1016/j.canlet.2023.216366

在 PubMed 查看 → 出版商原文（DOI）报告译文或资料问题 →