肿瘤抗原是诱导肿瘤特异性排斥的T细胞治疗的重要靶点。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。使用先进的质谱分析（MS），我们先前已鉴定出多个HLA-A类型的PDAC患者共享的与癌症相关的I类MHC结合表位。在本研究中，我们调查了其中一个表位LAMC2203-211，一个自然存在的未突变表位在LAMC2蛋白上。在使用LAMC2203-211肽刺激后，我们克隆了T细胞受体（TCR）并通过慢病毒载体将其转导到Jurkat人类T细胞系中。我们发现表达LAMC2203-211特异性TCR的Jurkat细胞对PDAC细胞具有有效的LAMC2特异性体外细胞毒效应。此外，对于携带HLA-A等位基因互配或不互配的PDAC患者来源的皮下或原位植入肿瘤的小鼠，通过输入LAMC2靶向T细胞，肿瘤生长以LAMC2依赖方式受到抑制。因此，我们已开发出一种基于LAMC2特异性TCR的T细胞疗法策略，可能适用于许多PDAC患者。这是首个采用质谱分析鉴定PDAC中天然CD8+ T细胞表位，并且可能作为PDAC免疫疗法靶点的研究。版权所有©2023年。由Elsevier B.V.出版。

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, LAMC2203-211, a naturally occurring nonmutated epitope on the LAMC2 protein. Following stimulation with the LAMC2203-211 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 LAMC2203-211-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.Copyright © 2023. Published by Elsevier B.V.