@misc{10481/108580,
year = {2025},
month = {11},
url = {https://hdl.handle.net/10481/108580},
abstract = {Increasing the quantity and immunogenicity of neoantigens in tumors is essential for advancing immunotherapy. However, engineering neoantigens remains challenging due to the need for precise, tumor-specific antigen modification without affecting normal cells. To tackle this challenge, we developed Short Precise-Encodable ADAR Recruiting (SPEAR) ADAR-engagers, an approach that uses short guide RNAs to engage the endogenous RNA editor ADAR1 and direct it to regions of mRNA targets known to encode MHC-presented peptides. By precisely editing adenosine-to-inosine (A-to-I) in these contexts, we effectively mutate specific epitopes into neoepitopes (which we now term “editopes”). As proof of concept, we targeted the known antigen MART-1 (Melanoma-Associated Antigen Recognized by T cells-1), and demonstrated that guided ADAR1 editing can generate immunogenic epitopes that activate T cells and promote tumor cell elimination. Building on this concept, we developed a computational pipeline to identify tumor-specific somatic mutations suitable for SPEAR-mediated editing. This strategy enables selective neoantigen generation in cancer cells, effectively increasing their apparent tumor mutational burden and potentially enhancing their susceptibility to immunotherapy.},
organization = {German Cancer Research Centre (DKFZ)},
organization = {National Institutes of Health, Bethesda, United States},
organization = {Bar-Ilan University, Israel},
organization = {Heidelberg University, Germany},
organization = {BioMed X Institute, Germany},
organization = {DKTK (German Cancer Consortium)},
organization = {Hertie Network of Excellence in Clinical Neuroscience},
organization = {University of Granada, Spain},
publisher = {bioRxiv preprint},
keywords = {neoantigen},
keywords = {RNA editing},
keywords = {ADAR1},
title = {Employing RNA editing to engineer personalized tumor-specific neoantigens (editopes)},
doi = {10.1101/2023.03.16.532918},
author = {Pecori, Riccardo and Casati, Beatrice and Merdler-Rabinowicz, Rona and Landesman, Netanel and Sanghvi, Khwab and Zens, Stefan and Kipfstuhl, Kai and Pinamonti, Veronica and Arnold, Annette and Lindner, John M. and Platten, Michael and Offringa, Rienk and Carretero Coca, Rafael and Ruppin, Eytan and Levanon, Erez Y. and Papavasiliou, Fotini Nina},
}