HERV-derived epitopes represent new targets for T-cell based immunotherapies in ovarian cancer

Abstract

AbstractBackgroundOvarian cancer represents the most lethal gynecological cancer with poor results of checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T cell epitopes for cancer immunotherapy regardless of the tumor mutational burden.MethodsA transcriptomic analysis based on RNA-sequencing (RNA-seq) was developed to quantify the expression of HERV-K sequences containing the selected epitopes. The presence of HERV-K/HML-2 Gag antigen was then assessed by immunohistochemistry (IHC) on tumor microarrays from ovarian cancer samples and normal ovarian tissues. A specific immunopeptidomics approach was developed to detect epitopes on HLA molecules. Epitope-specific CD8+T cells were quantified by multimer staining andin vitrotarget cell killing was evaluated using xCELLigence technology.In vivoantitumor efficacy of HERV-specific T cells was assessed in an avian embryo model.ResultsEpitope-containing HERV transcripts were significantly higher in ovarian cancers compared to normal tissues. The presence of HERV-K/HML-2 Gag antigen was confirmed by IHC in 20/40 (50%) ovarian cancers while no Gag expression was found in normal ovarian tissue samples. Immunopeptidomics analysis showed the presence of epitopes on HLA molecules on the surface of ovarian tumor cell lines but not on normal primary cells from critical tissues. HERV-specific T cells were detected among tumor infiltrating lymphocytes (TILs) from ovarian cancers, confirming the immunogenicity of these epitopes in patients.In vitro, HERV-specific T cells specifically killed ovarian cancer cells in an HLA class I-restricted manner while sparing normal HLA-A2-positive primary cells derived from critical tissues. Epitope-specific CD8+T cells exhibited a strong anti-tumoral activityin vivo, inducing a highly significant decrease in tumor volume in comparison with control groups.ConclusionThese results provide the preclinical rationale for developing T-cell based approaches against HERV-K-derived epitopes in ovarian cancer.Graphical abstractSome HERVs are specifically overexpressed in ovarian cancer compared to normal tissues.HERV-K/HML-2 Gag antigen is detected by immunohistochemistry in ovarian cancers but not in normal ovarian tissues. Furthermore, HERV-K-derived epitopes are presented on HLA molecules on the surface of ovarian cancer cells but not on normal cells.These epitopes are immunogenic in patients and induce high-avidity CD8+T cells that specifically kill ovarian cancer cellsin vitroandin vivowhile sparing normal cells.