Mass spectrometry driven exploration reveals nuances of neoepitope-driven tumor rejection.

Details

Serval ID
serval:BIB_77410C339277
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mass spectrometry driven exploration reveals nuances of neoepitope-driven tumor rejection.
Journal
JCI insight
Author(s)
Ebrahimi-Nik H., Michaux J., Corwin W.L., Keller G.L., Shcheglova T., Pak H., Coukos G., Baker B.M., Mandoiu I.I., Bassani-Sternberg M. (co-last), Srivastava P.K.
ISSN
2379-3708 (Electronic)
ISSN-L
2379-3708
Publication state
Published
Issued date
20/06/2019
Peer-reviewed
Oui
Volume
5
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Neoepitopes are the only truly tumor-specific antigens. Although potential neoepitopes can be readily identified using genomics, the neoepitopes that mediate tumor rejection constitute a small minority, and there is little consensus on how to identify them. Here, for the first time, we use a combination of genomics, unbiased discovery MS immunopeptidomics and targeted MS to directly identify neoepitopes that elicit actual tumor rejection in mice. We report that MS-identified neoepitopes are an astonishingly rich source of tumor rejection mediating neoepitopes. MS has also demonstrated unambiguously the presentation by MHC I, of confirmed tumor rejection neoepitopes which bind weakly to MHC I; this was done using DCs exogenously loaded with long peptides containing the weakly binding neoepitopes. Such weakly MHC I-binding neoepitopes are routinely excluded from analysis, and our demonstration of their presentation, and their activity in tumor rejection, reveals a broader universe of tumor-rejection neoepitopes than presently imagined. Modeling studies show that a mutation in the active neoepitope alters its conformation such that its T cell receptor-facing surface is significantly altered, increasing its exposed hydrophobicity. No such changes are observed in the inactive neoepitope. These results broaden our understanding of antigen presentation and help prioritize neoepitopes for personalized cancer immunotherapy.
Keywords
Antigen presentation, Dendritic cells, Immunology, Immunotherapy
Pubmed
Open Access
Yes
Create date
26/07/2019 15:43
Last modification date
11/12/2020 6:26
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