Identification of shared tumor epitopes from endogenous retroviruses inducing high-avidity cytotoxic T cells for cancer immunotherapy
Paola Bonaventura, Vincent Alcazer, Virginie Mutez, Laurie Tonon, Juliette Martin, Nicolas Chuvin, Emilie Michel, Rasha E. Boulos, Yann Estornes, Jenny Valladeau‐Guilemond, Alain Viari, Qing Wang, Christophe Caux, Stéphane Depil
Abstract
Human endogenous retroviruses (HERVs) represent 8% of the human genome. HERV products may represent tumor antigens relevant for cancer immunotherapy. We developed a bioinformatic approach to identify shared CD8 + T cell epitopes derived from cancer-associated HERVs in solid tumors. Six candidates among the most commonly shared HLA-A2 epitopes with evidence of translation were selected for immunological evaluation. In vitro priming assays confirmed the immunogenicity of these epitopes, which induced high-avidity CD8 + T cell clones. These T cells specifically recognize and kill HLA-A2 + tumor cells presenting HERV epitopes on HLA molecules, as demonstrated by mass spectrometry. Furthermore, epitope-specific CD8 + T cells were identified by dextramer staining among tumor-infiltrating lymphocytes from HLA-A2 + patients with breast cancer. Last, we showed that HERV-specific T cells lyse patient-derived organoids. These shared virus-like epitopes are of major interest for the development of cancer vaccines or T cell–based immunotherapies, especially in tumors with low/intermediate mutational burden.