Specific Increase in Potency via Structure-Based Design of a TCR

J Immunol. 2014 Sep 1;193(5):2587-99. doi: 10.4049/jimmunol.1302344. Epub 2014 Jul 28.

Abstract

Adoptive immunotherapy with Ag-specific T lymphocytes is a powerful strategy for cancer treatment. However, most tumor Ags are nonreactive "self" proteins, which presents an immunotherapy design challenge. Recent studies have shown that tumor-specific TCRs can be transduced into normal PBLs, which persist after transfer in ∼30% of patients and effectively destroy tumor cells in vivo. Although encouraging, the limited clinical responses underscore the need for enrichment of T cells with desirable antitumor capabilities prior to patient transfer. In this study, we used structure-based design to predict point mutations of a TCR (DMF5) that enhance its binding affinity for an agonist tumor Ag-MHC (peptide-MHC [pMHC]), Mart-1 (27L)-HLA-A2, which elicits full T cell activation to trigger immune responses. We analyzed the effects of selected TCR point mutations on T cell activation potency and analyzed cross-reactivity with related Ags. Our results showed that the mutated TCRs had improved T cell activation potency while retaining a high degree of specificity. Such affinity-optimized TCRs have demonstrated to be very specific for Mart-1 (27L), the epitope for which they were structurally designed. Although of somewhat limited clinical relevance, these studies open the possibility for future structural-based studies that could potentially be used in adoptive immunotherapy to treat melanoma while avoiding adverse autoimmunity-derived effects.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Epitopes, T-Lymphocyte* / chemistry
  • Epitopes, T-Lymphocyte* / genetics
  • Epitopes, T-Lymphocyte* / immunology
  • Humans
  • Lymphocyte Activation
  • MART-1 Antigen* / chemistry
  • MART-1 Antigen* / genetics
  • MART-1 Antigen* / immunology
  • Peptides* / chemistry
  • Peptides* / immunology
  • Point Mutation
  • Protein Engineering*
  • Receptors, Antigen, T-Cell* / chemistry
  • Receptors, Antigen, T-Cell* / genetics
  • Receptors, Antigen, T-Cell* / immunology
  • Structure-Activity Relationship

Substances

  • Epitopes, T-Lymphocyte
  • MART-1 Antigen
  • Peptides
  • Receptors, Antigen, T-Cell