Comprehensive mapping of identical sequences across human proteins emphasizes the widespread issue of shared epitopes in self-antigens

Shared epitopes pose safety and efficacy issues for T-cell immunotherapy. To characterize the extent of this problem, we performed a computational analysis establishing a complete atlas of shared identical sequences across the human and murine proteomes. Unlike bacterial or viral antigens, self-antigens, including tumor-associated antigens (TAAs), frequently contain sequences of sufficient length to generate identical epitopes in other self-proteins. Epitopes from these shared sequences can theoretically reduce target specificity, confound immunomonitoring studies, and contribute to pre-existing immune tolerance toward TAAs. Notably, a subset of TAAs identified in this atlas is free of this drawback, providing a new criterion for antigen prioritization in cancer immunotherapy. To facilitate the detection of shared sequences, a web server has been made available at https://epitopemapper.ircan.org/ and the open-source code at https://github.com/IRCAN/EpitopeMapper.