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Neoepitope formation through the generation of RNA-derived "editopes"

Casati, B.; Pinamonti, V.; Pecori, R.; Lindner, J. M.; Papavasiliou, F. N.

2023-03-19 cancer biology
10.1101/2023.03.16.532918 bioRxiv
Show 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.

Published in The EMBO Journal · training set

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