NeoScore integrates characteristics of the neoantigen:MHC class I interaction and expression to accurately prioritize immunogenic neoantigens

Abstract

AbstractAccurate prioritization of immunogenic neoantigens is key to developing personalized cancer vaccines and distinguishing those patients likely to respond to immune checkpoint inhibition. However, there is no consensus regarding which characteristics best predict neoantigen immunogenicity, and no model to date has both high sensitivity and specificity and a significant association with survival in response to immunotherapy. We address these challenges in the prioritization of immunogenic neoantigens by 1) identifying which neoantigen characteristics best predict immunogenicity, 2) integrating these characteristics into an immunogenicity score, NeoScore, and 3) demonstrating an improved association of the NeoScore with response to immune checkpoint inhibition compared to mutational burden. One thousand random and evenly split combinations of immunogenic and non-immunogenic neoantigens from a validated dataset were analyzed using a regularized regression model for characteristic selection. The selected characteristics, the dissociation constant and binding stability of the neoantigen:MHC class I complex and expression of the mutated gene in the tumor, were integrated into the NeoScore. A web application is provided for calculation of the NeoScore. The NeoScore results in improved, or equivalent, performance in four test datasets as measured by sensitivity, specificity, and area under the receiver operator characteristics curve compared to previous models. Among cutaneous melanoma patients treated with immune checkpoint inhibition, a high NeoScore had a greater association with improved survival compared to mutational burden. Overall, the NeoScore has the potential to improve neoantigen prioritization for the development of personalized vaccines and contribute to the determination of which patients are likely to respond to immunotherapy.