Abstract
The ability of mammals to mount adaptive immune responses culminating with the establishment of immunological memory is predicated on the ability of the mature T cell repertoire to recognize antigenic peptides presented by syngeneic MHC class I and II molecules. Although it is widely believed that mature T cells are highly skewed towards the recognition of antigenic peptides originating from genetically diverse (for example, foreign or mutated) protein-coding regions, preclinical and clinical data rather demonstrate that novel antigenic determinants efficiently recognized by mature T cells can emerge from a variety of non-mutational mechanisms. In this Review, we describe various mechanisms that underlie the formation of bona fide non-mutational neoantigens, such as epitope mimicry, upregulation of cryptic epitopes, usage of non-canonical initiation codons, alternative RNA splicing, and defective ribosomal RNA processing, as well as both enzymatic and non-enzymatic post-translational protein modifications. Moreover, we discuss the implications of the immune recognition of non-mutational neoantigens for human disease.
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Acknowledgements
We are indebted to V. Klapp for help preparing figures. L.J.S. is supported by the National Institutes of Health (NIH) (AG067581, AI146180, AI143976, AI137198, AI127869, AI153828, AR080593) and the Parkinson’s Foundation. L.G. is/has been supported (as a principal investigator (PI) unless otherwise indicated) by one R01 grant from the NIH/NCI (CA271915), by two Breakthrough Level 2 grants from the US DoD BCRP (BC180476P1, BC210945), by a grant from the STARR Cancer Consortium (I16-0064), by a Transformative Breast Cancer Consortium Grant from the US DoD BCRP (W81XWH2120034, PI: Formenti), by a U54 grant from NIH/NCI (CA274291, PI: Deasy, Formenti, Weichselbaum), by the 2019 Laura Ziskin Prize in Translational Research (ZP-6177, PI: Formenti) from the Stand Up to Cancer (SU2C), by a Mantle Cell Lymphoma Research Initiative (MCL-RI, PI: Chen-Kiang) grant from the Leukemia and Lymphoma Society (LLS), by a Rapid Response Grant from the Functional Genomics Initiative, by a pre-SPORE grant (PI: Demaria, Formenti) and a Clinical Trials Innovation Grant from the Sandra and Edward Meyer Cancer Center; by startup funds from the Department of Radiation Oncology at Weill Cornell Medicine, by industrial collaborations with Lytix Biopharma, Promontory, and Onxeo, as well as by donations from Promontory, the Luke Heller TECPR2 Foundation, SOTIO Biotech a.s., Lytix Biopharma, Onxeo, Ricerchiamo, and Noxopharm. L.S. is supported by the NIH (AI153828, AI146180, no. AI137198, AI137198-S, AI169723, AI134696, AG031782, AT011419, AR081493, AI170897) and the Cure Alzheimer’s Foundation.
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L.G. and L.S. conceived the article. L.J.S., L.G., and L.S. wrote the first version of the manuscript with constructive input from C.C.
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L.G. declares holding research contracts with Lytix Biopharma, Promontory and Onxeo, and has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation, and holds Promontory stock options. The other authors declare no competing interests.
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Stern, L.J., Clement, C., Galluzzi, L. et al. Non-mutational neoantigens in disease. Nat Immunol 25, 29–40 (2024). https://doi.org/10.1038/s41590-023-01664-1
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DOI: https://doi.org/10.1038/s41590-023-01664-1
