期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 11, 页码 2231-2248出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20141308
关键词
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资金
- Cancer Research Institute, New York
- Northeastern Utilities Chair in Experimental Oncology
- Personalized Immunotherapy Core Interest Group of the Connecticut Institute for Clinical and Translational Science
- SPARK
- National Science Foundation [IIS-0916948]
- National Institutes of Health [GM067079, GM103773]
- Life Technologies [AG110891]
- Agriculture and Food Research Initiative Competitive Grant from USDA National Institute of Food and Agriculture [2011-67016-30331]
- NIFA [579659, 2011-67016-30331] Funding Source: Federal RePORTER
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.
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