Structural dissimilarity from self drives neoepitope escape from immune tolerance

Jason R. Devlin, Jesus A. Alonso, Cory M. Ayres, Grant L.J. Keller, Sara Bobisse, Craig W. Vander Kooi, George Coukos, David Gfeller, Alexandre Harari, Brian M. Baker

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

T-cell recognition of peptides incorporating nonsynonymous mutations, or neoepitopes, is a cornerstone of tumor immunity and forms the basis of new immunotherapy approaches including personalized cancer vaccines. Yet as they are derived from self-peptides, the means through which immunogenic neoepitopes overcome immune self-tolerance are often unclear. Here we show that a point mutation in a non-major histocompatibility complex anchor position induces structural and dynamic changes in an immunologically active ovarian cancer neoepitope. The changes pre-organize the peptide into a conformation optimal for recognition by a neoepitope-specific T-cell receptor, allowing the receptor to bind the neoepitope with high affinity and deliver potent T-cell signals. Our results emphasize the importance of structural and physical changes relative to self in neoepitope immunogenicity. Considered broadly, these findings can help explain some of the difficulties in identifying immunogenic neoepitopes from sequence alone and provide guidance for developing novel, neoepitope-based personalized therapies. [Figure not available: see fulltext.]

Original languageEnglish
Pages (from-to)1269-1276
Number of pages8
JournalNature Chemical Biology
Volume16
Issue number11
DOIs
StatePublished - Nov 1 2020

Bibliographical note

Funding Information:
We thank L. Hellman for assistance with biophysical and structural work, R. Genolet for assistance with TCR sequences and C. Klebanoff for comments on the manuscript. B.M.B. acknowledges support from the NIGMS, NIH (grant no. R35GM118166). A.H. acknowledges support from the Swiss National Science Foundation (grant no. 310030– 182384). D.G. acknowledges support from Swiss Cancer League (grant no. KFS-4104-02-2017). J.R.D. and G.L.J.K. acknowledge support from the Indiana CTSI, funded by the NIH (grant no. UL1TR002529). X-ray diffraction data were collected at the Advanced Photon Source, supported by DOE contract no. DE-AC02-06CH11357, and the NE-CAT and SER-CAT beamlines, supported by member institutions and NIH grants no. P30GM124165, no. S10OD021527, no. S10RR25528 and no. S10RR028976.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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