Predicting Immunogenic Tumor Neoantigens With Combined Mass Spectrometry and Exome Sequencing

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Peptides containing tumor somatic mutations are potentially immunogenic if presented on major histocompatibility complex class I molecules (MHC-I), and it has been shown that such mutant peptides act as T-cell epitopes.  In a study reported in Nature, Yadav and colleagues developed an approach combining whole-exome and transcriptome sequencing analysis with mass spectrometry, which enabled them to identify neoepitopes in two common mouse tumor models. Of the  >1,300 amino acid changes identified, approximately 13% were predicted to bind MHC-I, with a small fraction of these being confirmed by mass spectrometry. The identified peptides were structurally modeled bound to MHC-I, with the mutations that were solvent-exposed and thus accessible to T-cell antigen receptors being predicted to be immunogenic. Every predicted immunogenic peptide produced a therapeutically active T-cell response when used as a vaccine in mice. The predictions also permitted development of peptide-MHC-I dextramers, which allowed monitoring of kinetics and distribution of the antitumor T-cell response before and after vaccination.

The investigators concluded: “These findings indicate that a suitable prediction algorithm may provide an approach for the pharmacodynamic monitoring of T-cell responses as well as for the development of personalized vaccines in cancer patients.” ■

Yadav M, et al: Nature 515:572-576, 2014.




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