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bioRxiv · 10.1101/2022.03.14.484285

MHC-I binding affinity derived metrics fail to predict tumor specific neoantigen immunogenicity

Nibeyro, G.·Girotti, M. R.·Prato, L.·Moron, V. G.·Lujan, H. D.·Fernandez, E. A.
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Abstract

Tumor-specific antigens emerging through somatic genomic rearrangements, known as neoantigens, play a critical role in current anticancer immunotherapy. They may or may not elicit an immune response when presented on the tumor cell surface bound to the MHC-I molecule, whose strength has been assumed as an indicator of immunogenicity. Several in silico peptide-MHC-I binding affinity predictors are used to prioritize putative immunogenic neoantigens to be experimentally and clinically explored either as biomarkers or targets for anticancer vaccines. This claims for a fair evaluation of such predictors, making essential the development of appropriate databases with experimentally validated, immunogenic/non-immunogenic neoantigens. Thus far, such a database is lacking. We herein present ITSNdb, a new and curated immunogenic neoantigen database and use it to benchmark current neoantigen immunogenicity predictors. Benchmark results failed to support the application of the predicted peptide- MHC-I binding affinity or its derived metrics as a tool to estimate neoantigen immunogenicity and the tumor neoantigen burden as an immunotherapy response biomarker. Moreover, binding affinity based immunogenicity definition leads to identifying wild-type peptide counterparts as predictors of immunotherapy response. We demonstrate that MHC-I binding affinity is insufficient to define neoantigen immunogenicity, despite being necessary for neoantigen tumor cell presentation suggesting that a paradigm shift for the emergence of new rules to identify immunogenic neoantigens is required.

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Nibeyro, G., Girotti, M. R., Prato, L., Moron, V. G., Lujan, H. D., Fernandez, E. A.. 2022-03-17. MHC-I binding affinity derived metrics fail to predict tumor specific neoantigen immunogenicity. https://doi.org/10.1101/2022.03.14.484285

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