title: Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity.
abstract: The mutational repertoire of cancers creates the neoepitopes that make cancers immunogenic. Here, we introduce two novel tools that identify, with relatively high accuracy, the small proportion of neoepitopes (among the hundreds of potential neoepitopes) that protect the host through an antitumor T cell response. The two tools consist of (a) the numerical difference in NetMHC scores between the mutated sequences and their unmutated counterparts, termed the differential agretopic index, and (b) the conformational stability of the MHC I-peptide interaction. Mechanistically, these tools identify neoepitopes that are mutated to create new anchor residues for MHC binding, and render the overall peptide more rigid. Surprisingly, the protective neoepitopes identified here elicit CD8-dependent immunity, even though their affinity for K(d) is orders of magnitude lower than the 500-nM threshold considered reasonable for such interactions. These results greatly expand the universe of target cancer antigens and identify new tools for human cancer immunotherapy.
authors.affiliation: Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030.
authors.forename: Fei
authors.initials: F
authors.lastname: Duan
authors.affiliation: Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269.
authors.forename: Jorge
authors.initials: J
authors.lastname: Duitama
authors.affiliation: Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269.
authors.forename: Sahar
authors.initials: S
authors.lastname: Al Seesi
authors.affiliation: Department of Chemistry and Biochemistry and Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Ayres
authors.affiliation: Department of Chemistry and Biochemistry and Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Corcelli
authors.affiliation: Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030.
authors.forename: Arpita P
authors.initials: AP
authors.lastname: Pawashe
authors.affiliation: Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Blanchard
authors.affiliation: Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030.
authors.forename: David
authors.initials: D
authors.lastname: McMahon
authors.affiliation: LaJolla Institute of Allergy and Immunology, La Jolla, CA 92037.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: LaJolla Institute of Allergy and Immunology, La Jolla, CA 92037.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Department of Chemistry and Biochemistry and Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Baker
authors.affiliation: Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269 Srivastava@uchc.edu ion@engr.uconn.edu.
authors.forename: Ion I
authors.initials: II
authors.lastname: Mandoiu
authors.affiliation: Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030 Srivastava@uchc.edu ion@engr.uconn.edu.
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Srivastava
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D004195:Disease Models, Animal; D000939:Epitopes / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D018740:Genetic Heterogeneity; D023281:Genomics / Q000379:methods; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000276:immunology; D051379:Mice; D008958:Models, Molecular; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology*; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics / Q000276:immunology; D011487:Protein Conformation; D059467:Transcriptome
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes