HLA-DR Presentation of the Tumor Antigen MSLN Associates with Clinical Outcome of Ovarian Cancer Patients

SIMPLE SUMMARY: The immunopeptidome represents the entirety of peptides that are presented on the surface of cells on human leukocyte antigen (HLA) molecules and are recognized by the T-cell receptors of CD4(+) and CD8(+) T-cells. Malignant cells present tumor-associated antigens essential for tumor immune surveillance, which can be targeted by T-cell-based immunotherapy approaches. For ovarian carcinomas, various tumor-associated antigens, such as Mucin-16 and Mesothelin, have been described. The aim of our study is to analyze immunopeptidome-defined tumor antigen presentation in ovarian carcinoma patients in relation to clinical characteristics and disease outcomes to define potential biomarkers. Our work demonstrates the central role of HLA-DR-restricted peptide presentation of the tumor antigen Mesothelin and of CD4(+) T-cell responses for tumor immune surveillance, and underlines Mesothelin as a prime target antigen for novel immunotherapeutic approaches for ovarian carcinoma patients. ABSTRACT: 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.