title: HLA ligandomics identifies histone deacetylase 1 as target for ovarian cancer immunotherapy.
abstract: The recent approval of clincially effective immune checkpoint inhibitors illustrates the potential of cancer immunotherapy. A challenging task remains the identification of specific targets guiding immunotherapy. Facilitated by technical advances, the direct identification of physiologically relevant targets is enabled by analyzing the HLA ligandome of cancer cells. Since recent publications demonstrate the immunogenicity of ovarian cancer (OvCa), immunotherapies, including peptide-based cancer vaccines, represent a promising treatment approach. To identify vaccine peptides, we employed a combined strategy of HLA ligandomics in high-grade serous OvCa samples and immunogenicity analysis. Only few proteins were naturally presented as HLA ligands on all samples analyzed, including histone deacetylase (HDAC) 1 and 2. In vitro priming of CD8(+) T cells demonstrated that two HDAC1/2-derived HLA ligands can induce T-cell responses, capable of killing HLA-matched tumor cells. High HDAC1 expression shown by immunohistochemistry in 136 high-grade serous OvCa patients associated with significantly reduced overall survival (OS), whereas patients with high numbers of CD3(+) tumor-infiltrating lymphocytes (TILs) in the tumor epithelium and CD8(+) TILs in the tumor stroma showed improved OS. However, correlating HDAC1 expression with TILs, high levels of TILs abrogated the impact of HDAC1 on OS. This study strengthens the role of HDAC1/2 as an important tumor antigen in OvCa, demonstrating its impact on OS in a large cohort of OvCa patients. We further identified two immunogenic HDAC1-derived peptides, which frequently induce multi-functional T-cell responses in many donors, suitable for future multi-peptide vaccine trials in OvCa patients.
authors.affiliation: Department of Immunology, Institute of Cell Biology, University of Tübingen , Tübingen, Germany.
authors.forename: Janet Kerstin
authors.initials: JK
authors.lastname: Peper
authors.affiliation: Institute of Pathology, University Hospital of Tübingen , Tübingen, Germany.
authors.forename: Hans-Christian
authors.initials: HC
authors.lastname: Bösmüller
authors.affiliation: Department of Immunology, Institute of Cell Biology, University of Tübingen , Tübingen, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Schuster
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital of Tübingen , Tübingen, Germany.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Gückel
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital of Tübingen , Tübingen, Germany.
authors.forename: Helen
authors.initials: H
authors.lastname: Hörzer
authors.affiliation: Department of Immunology, Institute of Cell Biology, University of Tübingen , Tübingen, Germany.
authors.forename: Kevin
authors.initials: K
authors.lastname: Roehle
authors.affiliation: Department of Clinical and Experimental Transfusion Medicine, University Hospital of Tübingen , Tübingen, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Schäfer
authors.affiliation: Department of Obstetrics and Gynecology, University Hospital of Tübingen , Tübingen, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wagner
authors.affiliation: Department of Immunology, Institute of Cell Biology, University of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Tübingen, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Rammensee
authors.affiliation: Department of Immunology, Institute of Cell Biology, University of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Tübingen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Stevanović
authors.affiliation: Institute of Pathology, University Hospital of Tübingen, Tübingen, Germany; German Cancer Consortium (DKTK), DKFZ partner site Tübingen, Tübingen, Germany.
authors.forename: Falko
authors.initials: F
authors.lastname: Fend
authors.affiliation: Institute of Pathology, University Hospital of Tübingen , Tübingen, Germany.
authors.forename: Annette
authors.initials: A
authors.lastname: Staebler
keywords: HLA; Histone deacetylase; immunotherapy; ovarian cancer; peptide vaccination