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

Immune Surveillance of Acute Myeloid Leukemia Is Mediated by HLA-Presented Antigens on Leukemia Progenitor Cells

“…Previous reports showed that spontaneous and vaccine-induced tumor-specific T-cell responses are predominantly mediated by CD4 + T cells ( 24, 50–53 ). Furthermore, HLA class II–restricted tumor antigen presentation and antigen-specific CD4 + T-cell responses correlate with clinical outcome of patients with cancer ( 54, 55 ). HSPCs present MHC class II–restricted antigens that interact with antigen-specific CD4 + T cells in mice ( 10 ).…”

Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer

“…In different types of cancer, including ovarian cancer, the expression of MHC-II is associated with a better patient outcome, highlighting (as in other cancer types) the relevance of the T CD4+ lymphocyte activity as well as T CD8+ cells. [70][71][72][73][74][75] Furthermore, PDL-1+ tumor cells were observed more frequently in all groups of treated mice, especially in niraparib and CMP/niraparib treated tumor-bearing mice, with the particularity that the expression level of this protein slightly decreased in the CMP group (Figure 7e). Additionally, these tumor cells expressed MHC-II with a similar trend to that observed in total live HGSC cells (Supplementary Figure 6a).…”

Comprehensive analysis of the interaction of antigen presentation during anti‐tumour immunity and establishment of AIDPS systems in ovarian cancer

“…T cells play a crucial role in immune surveillance by identifying tumourassociated antigens presented on the surface of cancer cells. In the case of ovarian cancer, research indicates that Mucin-16 (MUC16) and Mesothelin (MSLN) are significant tumour antigens, presented respectively by human leukocyte antigen-I and human leukocyte antigen-II molecules 40. Therefore, we postulate that the pivotal role of antigen presentation in ovarian cancer lies in the recognition of tumour-associated antigens and their presentation to T cells within the immune system.…”