Devlin et al. showed comparably strong binding of a patient-specific cancer neoepitope HHATp8F and wild-type (WT) peptides to HLA-A*02:06, but faster and stronger binding of HHATp8F–HLA-A complexes to recombinant soluble (rs) neoepitope-specific TCRαβ derived from HHATp8F-specific intratumoral T cells. Co-crystallization and molecular dynamic simulations of HLA-A*02:06–HHATp8F or WT complexes, and those complexed with rsTCR showed that a reoriented Trp sidechain two amino acids away from the conservative Leu-to-Phe substitution induced changes from the C-terminal end to the peptide central core to enable enhanced HHATp8F TCR recognition.
Contributed by Paula Hochman
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.
Author Info: (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. (2) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN,
Author Info: (1) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. (2) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. (3) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. (4) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. (5) Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (6) Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY, USA. (7) Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (8) Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. Swiss Institute of Bioinformatics, Lausanne, Switzerland. (9) Department of Oncology UNIL CHUV, Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland. Center of Experimental Therapeutics, Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. (10) Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, USA. brian-baker@nd.edu.
