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J Exp Med. 2014 Oct 20;211(11):2231-48. doi: 10.1084/jem.20141308. Epub 2014 Sep 22.

Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity.

Author information

1
Department of Immunology and Carole and Ray Neag Comprehensive Cancer Center, University of Connecticut School of Medicine, Farmington, CT 06030.
2
Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269.
3
Department of Chemistry and Biochemistry and Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556.
4
LaJolla Institute of Allergy and Immunology, La Jolla, CA 92037.
5
Department of Computer Science and Engineering, University of Connecticut, Storrs, CT 06269 Srivastava@uchc.edu ion@engr.uconn.edu.
6
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.

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.

PMID:
25245761
PMCID:
PMC4203949
DOI:
10.1084/jem.20141308
[Indexed for MEDLINE]
Free PMC Article

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