To improve identification of protective neoepitopes, Custodio et al. analyzed multiple structural features of a strongly, a moderately, and a non-protective neoepitope (and their WT counterparts) from a murine model. All three epitopes contained 2o anchor mutations, which enhanced MHC I affinity, and there was an inverse relationship between protection and affinity of the cognate WT peptide. Structurally, the peptide backbone did not differ much from WT for any of the neoepitopes, but the most protective was more rigid in the MHC groove and presented an exposed aromatic side chain. An AI-assisted structural modeling program (based on AlphaFold) was best at predicting the observed structure.
Contributed by Ed Fritsch
ABSTRACT: Neoepitopes arising from amino acid substitutions due to single nucleotide polymorphisms are targets of T cell immune responses to cancer and are of significant interest in the development of cancer vaccines. However, understanding the characteristics of rare protective neoepitopes that truly control tumor growth has been a challenge, due to their scarcity as well as the challenge of verifying true, neoepitope-dependent tumor control in humans. Taking advantage of recent work in mouse models that circumvented these challenges, here, we compared the structural and physical properties of neoepitopes that range from fully protective to immunologically inactive. As neoepitopes are derived from self-peptides that can induce immune tolerance, we studied not only how the various neoepitopes differ from each other but also from their wild-type counterparts. We identified multiple features associated with protection, including features that describe how neoepitopes differ from self as well as features associated with recognition by diverse T cell receptor repertoires. We demonstrate both the promise and limitations of neoepitope structural analysis and predictive modeling and illustrate important aspects that can be incorporated into neoepitope prediction pipelines.
Author Info: (1) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (2) Department of Chemistry and Biochemistry
Author Info: (1) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (2) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (3) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (4) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (5) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (6) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (7) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556. (8) Department of Immunology, and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030. (9) Department of Chemistry and Biochemistry and the Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
