Design of T-cell receptor libraries with diverse binding properties to examine adoptive T-cell responses

A. S. Chervin, J. D. Stone, C. M. Soto, B. Engels, H. Schreiber, E. J. Roy, D. M. Kranz

Research output: Contribution to journalArticle

Abstract

Adoptive T-cell therapies have shown significant promise in the treatment of cancer and viral diseases. One approach, which introduces antigen-specific T-cell receptors (TCRs) into ex vivo activated T cells, is designed to overcome central tolerance mechanisms that prevent responses by endogenous T-cell repertoires. Studies have suggested that use of higher-affinity TCRs against class I major histocompatibility complex antigens could drive the activity of both CD4 + and CD8 + T cells, but the rules that govern the TCR binding optimal for in vivo activity are unknown. Here, we describe a high-throughput platform of 'reverse biochemistry' whereby a library of TCRs with a wide range of binding properties to the same antigen is introduced into T cells and adoptively transferred into mice with antigen-positive tumors. Extraction of RNA from tumor-infiltrating lymphocytes (TILs) or lymphoid organs allowed high-throughput sequencing to determine which TCRs were selected in vivo. The results showed that CD8 + T cells expressing the highest-affinity TCR variants were deleted in both the TIL population and in peripheral lymphoid tissues. In contrast, these same high-affinity TCR variants were preferentially expressed within CD4 + T cells in the tumor, suggesting they had a role in antigen-specific tumor control. The findings thus revealed that the affinity of the transduced TCRs controlled the survival and tumor infiltration of the transferred T cells. Accordingly, the TCR library strategy enables rapid assessment of TCR-binding properties that promote peripheral T-cell survival and tumor elimination.

Original languageEnglish (US)
Pages (from-to)634-644
Number of pages11
JournalGene therapy
Volume20
Issue number6
DOIs
StatePublished - Jun 1 2013

Keywords

  • Adoptive T-cell therapy
  • Affinity engineering
  • T-cell display
  • TCR
  • Tumor targeting

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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