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



Current Issue

Published September 22, 2014 // JEM vol. 211 no. 11 2231-2248 
The Rockefeller University Press, doi: 10.1084/jem.20141308

© 2014 Duan et al.

• Article

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

1. Fei Duan,1 
2. Jorge Duitama,2 
3. Sahar Al Seesi,2 
4. Cory M. Ayres,3 
5. Steven A. Corcelli,3
6. Arpita P. Pawashe,1 
7. Tatiana Blanchard,1 
8. David McMahon,1 
9. John Sidney,4
10. Alessandro Sette,4 
11. Brian M. Baker,3 
12. Ion I. Mandoiu,2 and 
13. Pramod K. Srivastava1

+Author Affiliations

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

+Author Notes

• F. Duan, J. Duitama, and S. Al Seesi contributed equally to this paper.
• J. Duitama’s present address is Agrobiodiversity Research Area, International Center for Tropical Agriculture (CIAT), 6713 Cali, Colombia.

1. CORRESPONDENCE Pramod Srivastava: Srivastava@uchc.edu OR Ion I. Mandoiu: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.

• Submitted: 11 July 2014
• Accepted: 5 September 2014

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