Employing RNA editing to engineer personalized tumor-specific neoantigens (editopes).
| Title: | Employing RNA editing to engineer personalized tumor-specific neoantigens (editopes). |
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| Authors: | Pecori R; Division of Immune Diversity, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Casati B; Division of Immune Diversity, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Merdler-Rabinowicz R; Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States.; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel.; Landesman N; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel.; Sanghvi K; Division of Neuroimmunology and Brain Tumor Immunology, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Zens S; Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; DKFZ Drug Discovery Lab (D3Lab), German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Kipfstuhl K; Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; DKFZ Drug Discovery Lab (D3Lab), German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Pinamonti V; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany.; BioMed X Institute, 69120 Heidelberg, Germany.; Current affiliation: Department of Experimental Oncology, European Institute of Oncology IRCCS, Milan, Italy.; Arnold A; Division of Immune Diversity, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Lindner JM; BioMed X Institute, 69120 Heidelberg, Germany.; Platten M; Division of Neuroimmunology and Brain Tumor Immunology, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; DKTK (German Cancer Consortium) Clinical Cooperation Unit (CCU) Neuroimmunology and Brain Tumor Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Neurology, Medical Faculty Mannheim, MCTN, University of Heidelberg, Mannheim, Germany.; German Cancer Consortium (DKTK), DKFZ, Core Center Heidelberg, Germany.; Hertie Network of Excellence in Clinical Neuroscience.; DKFZ-Hector Cancer Institute at University Medical Center Mannheim, Mannheim, Germany.; Helmholtz Institute for Translational Oncology (HI-TRON) Mainz, German Cancer Research Center, Mainz, Germany.; Offringa R; Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; DKFZ Drug Discovery Lab (D3Lab), German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Carretero R; Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany.; Department of Biochemistry, molecular Biology 3 and immunology. University of Granada, Spain.; Ruppin E; Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States.; Levanon EY; Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel.; Papavasiliou FN; Division of Immune Diversity, German Cancer Research Centre (DKFZ), Heidelberg, 69120, Germany. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2025 Nov 12. Date of Electronic Publication: 2025 Nov 12. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| 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. |
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| Entry Date(s): | Date Created: 20251126 Date Completed: 20251211 Latest Revision: 20251211 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC12642233 |
| DOI: | 10.1101/2023.03.16.532918 |
| PMID: | 41292723 |
| Database: | MEDLINE |
Journal Article; Preprint