I-restricted Antigen Research Articles

Abstract 1972: Clinical implications of HLA expression and immunopeptidome-presented tumor antigens in ovarian carcinoma

Abstract Ovarian carcinoma (OvCa) is the seventh most common malignancy in women and the eighth leading cause of cancer-related deaths worldwide. In a previous study, we characterized the antigenic landscape of ovarian carcinoma by mass spectrometry-based immunopeptidomics and identified novel OvCa-associated tumor antigens, including Mucin-16 (MUC-16) and Mesothelin (MSLN) with the aim to develop novel T cell-based immunotherapies (Schuster et al. PNAS 2017). Here, we analyzed the immunopeptidomics data of this OvCa cohort in relation to clinical patient characteristics and disease outcome. Analysis included 43 OvCa patients with respective immunopeptidomics and RNA sequencing data, comprising immunopeptidome diversity, tumor antigen presentation and expression (MUC16, MSLN) as well as HLA mRNA expression.Analyzing HLA class I-restricted tumor antigen presentation in relation to clinical data, we could show that nodal-positive patients presented more frequently HLA-restricted peptides derived from the tumor antigen MUC16 (p = 0.0087) and showed significantly increased numbers of unique MUC16-derived HLA-presented peptides within the total immunopeptidome (p = 0.042) compared to nodal-negative patients. No significant difference in HLA class I immunopeptidome diversity, overall tumor antigen presentation, and expression was observed for histological subtypes, grading, or the prevalence of distant metastases. For HLA class II-restricted tumor antigen presentation and HLA expression in relation to clinical data, we observed a more diverse HLA class II immunopeptidome in terms of different HLA class II-presented peptides (p = 0.011) for patients with high tumor grading (G3) compared to low/intermediate (G1/G2) grading. In line, the tumors of these patients also presented an increased number of different MSLN-derived HLA class II-restricted peptides (p = 0.021). No significant difference in HLA class II immunopeptidome diversity, tumor antigen presentation and expression was seen for the prevalence of distant metastasis, histological subtypes, or nodal positivity.Of note, patients presenting MSLN-derived peptides in their immunopeptidome showed a significantly prolonged recurrence-free survival (RFS, p = 0.011). In addition, patients exhibiting a high expression of HLA-DR showed a significantly increased RFS (p = 0.018 for HLA-DRA, p = 0.0031 for HLA-DRB).In conclusion, this work provides first insights on the relation of immunopeptidomic characteristics, comprising HLA expression and tumor antigen presentation, with clinical characteristics and disease outcome of OvCa patients. The observed correlation of HLA-DR expression and HLA class II tumor antigen presentation with prolonged RFS indicates a central role of CD4+ T cell responses for anti-tumor immune surveillance in ovarian cancer. Citation Format: Christian M. Tegeler, Jonas S. Heitmann, Helmut R. Salih, Juliane S. Walz, Annika Nelde. Clinical implications of HLA expression and immunopeptidome-presented tumor antigens in ovarian carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1972.

Optimized Whole Genome Association Scanning for Discovery of HLA Class I-Restricted Minor Histocompatibility Antigens

Patients undergoing allogeneic stem cell transplantation as treatment for hematological diseases face the risk of Graft-versus-Host Disease as well as relapse. Graft-versus-Host Disease and the favorable Graft-versus-Leukemia effect are mediated by donor T cells recognizing polymorphic peptides, which are presented on the cell surface by HLA molecules and result from single nucleotide polymorphism alleles that are disparate between patient and donor. Identification of polymorphic HLA-binding peptides, designated minor histocompatibility antigens, has been a laborious procedure, and the number and scope for broad clinical use of these antigens therefore remain limited. Here, we present an optimized whole genome association approach for discovery of HLA class I minor histocompatibility antigens. T cell clones isolated from patients who responded to donor lymphocyte infusions after HLA-matched allogeneic stem cell transplantation were tested against a panel of 191 EBV-transformed B cells, which have been sequenced by the 1000 Genomes Project and selected for expression of seven common HLA class I alleles (HLA-A∗01:01, A∗02:01, A∗03:01, B∗07:02, B∗08:01, C∗07:01, and C∗07:02). By including all polymorphisms with minor allele frequencies above 0.01, we demonstrated that the new approach allows direct discovery of minor histocompatibility antigens as exemplified by seven new antigens in eight different HLA class I alleles including one antigen in HLA-A∗24:02 and HLA-A∗23:01, for which the method has not been originally designed. Our new whole genome association strategy is expected to rapidly augment the repertoire of HLA class I-restricted minor histocompatibility antigens that will become available for donor selection and clinical use to predict, follow or manipulate Graft-versus-Leukemia effect and Graft-versus-Host Disease after allogeneic stem cell transplantation.