Tegeler Christian M, Scheid Jonas, Rammensee Hans-Georg, Salih Helmut R, Walz Juliane S, Heitmann Jonas S, Nelde Annika
Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK), Department of Internal Medicine, University Hospital Tübingen, 72076 Tübingen, Germany.
Department of Obstetrics and Gynecology, University Hospital Tübingen, 72076 Tübingen, Germany.
Cancers (Basel). 2022 Apr 30;14(9):2260. doi: 10.3390/cancers14092260.
T-cell recognition of HLA-presented antigens is central for the immunological surveillance of malignant disease and key for the development of novel T-cell-based immunotherapy approaches. In recent years, large-scale immunopeptidome studies identified naturally presented tumor-associated antigens for several malignancies. Regarding ovarian carcinoma (OvCa), Mucin-16 (MUC16) and Mesothelin (MSLN) were recently described as the top HLA class I- and HLA class II-presented tumor antigens, respectively. Here, we investigate the role and impact of immunopeptidome-presented tumor antigens on the clinical outcomes of 39 OvCa patients with a follow-up time of up to 50 months after surgery. Patients with a HLA-restricted presentation of high numbers of different MSLN-derived peptides on their tumors exhibited significantly prolonged progression-free (PFS) and overall survival (OS), whereas the presentation of MUC16-derived HLA class I-restricted peptides had no impact. Furthermore, a high HLA-DRB gene expression was associated with increased PFS and OS. In line, in silico prediction revealed that MSLN-derived HLA class II-presented peptides are predominantly presented on HLA-DR allotypes. In conclusion, the correlation of MSLN tumor antigen presentation and HLA-DRB gene expression with prolonged survival indicates a central role of CD4 T-cell responses for tumor immune surveillance in OvCa, and highlights the importance of immunopeptidome-guided tumor antigen discovery.
T细胞对HLA呈递抗原的识别是恶性疾病免疫监视的核心，也是新型基于T细胞的免疫治疗方法发展的关键。近年来，大规模免疫肽组学研究确定了几种恶性肿瘤中自然呈递的肿瘤相关抗原。关于卵巢癌（OvCa），粘蛋白-16（MUC16）和间皮素（MSLN）最近分别被描述为HLA I类和HLA II类呈递的顶级肿瘤抗原。在此，我们研究了免疫肽组呈递的肿瘤抗原对39例OvCa患者临床结局的作用和影响，这些患者术后随访时间长达50个月。肿瘤上大量不同MSLN衍生肽呈HLA限制性呈递的患者表现出显著延长的无进展生存期（PFS）和总生存期（OS），而MUC16衍生的HLA I类限制性肽的呈递则没有影响。此外，高HLA-DRB基因表达与PFS和OS增加相关。同样，计算机模拟预测显示，MSLN衍生的HLA II类呈递肽主要呈递于HLA-DR同种异型上。总之，MSLN肿瘤抗原呈递和HLA-DRB基因表达与生存期延长之间的相关性表明CD4 T细胞反应在OvCa肿瘤免疫监视中起核心作用，并突出了免疫肽组引导的肿瘤抗原发现的重要性。
