Unbiased Identification of T-Cell Receptors Targeting Immunodominant Peptide-MHC Complexes for T-Cell Receptor Immunotherapy

Hum Gene Ther. 2017 Dec;28(12):1158-1168. doi: 10.1089/hum.2017.122. Epub 2017 Sep 26.

Abstract

T-cell receptor (TCR) immunotherapy uses T cells engineered with new TCRs to enable detection and killing of cancer cells. Efficacy of TCR immunotherapy depends on targeting antigenic peptides that are efficiently presented by the best-suited major histocompatibility complex (MHC) molecules of cancer cells. However, efficient strategies are lacking to easily identify TCRs recognizing immunodominant peptide-MHC (pMHC) combinations utilizing any of the six possible MHC class I alleles of a cancer cell. We generated an MHC cell library and developed a platform approach to detect, isolate, and re-express TCRs specific for immunodominant pMHCs. The platform approach was applied to identify a human papillomavirus (HPV16) oncogene E5-specific TCR, recognizing a novel, naturally processed pMHC (HLA-B*15:01) and a cytomegalovirus-specific TCR targeting an immunodominant pMHC (HLA-B*07:02). The platform provides a useful tool to isolate in an unbiased manner TCRs specific for novel and immunodominant pMHC targets for use in TCR immunotherapy.

Keywords: MHC cell library; T cell receptor (TCR) discovery; TCR gene therapy; human papillomavirus ES; immunodominance; immunotherapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer / methods*
  • HLA-B15 Antigen* / genetics
  • HLA-B15 Antigen* / immunology
  • HLA-B7 Antigen* / genetics
  • HLA-B7 Antigen* / immunology
  • Humans
  • K562 Cells
  • Neoplasms* / genetics
  • Neoplasms* / immunology
  • Neoplasms* / pathology
  • Neoplasms* / therapy
  • Peptides / genetics
  • Peptides / immunology*
  • Receptors, Antigen, T-Cell* / genetics
  • Receptors, Antigen, T-Cell* / immunology
  • T-Lymphocytes / immunology*

Substances

  • HLA-B15 Antigen
  • HLA-B7 Antigen
  • Peptides
  • Receptors, Antigen, T-Cell