High-throughput identification of antigen-specific TCRs by TCR gene capture

Carsten Linnemann, Bianca Heemskerk, Pia Kvistborg, Roelof J.C. Kluin, Dmitriy A. Bolotin, Xiaojing Chen, Kaspar Bresser, Marja Nieuwland, Remko Schotte, Samira Michels, Raquel Gomez-Eerland, Lorenz Jahn, Pleun Hombrink, Nicolas Legrand, Chengyi Jenny Shu, Ilgar Z. Mamedov, Arno Velds, Christian U. Blank, John B.A.G. Haanen, Maria A. TurchaninovaRon M. Kerkhoven, Hergen Spits, Sine Reker Hadrup, Mirjam H.M. Heemskerk, Thomas Blankenstein, Dmitriy M. Chudakov, Gavin M. Bendle, Ton N.M. Schumacher

Research output: Contribution to journalArticlepeer-review

126 Citations (Scopus)

Abstract

The transfer of T cell receptor (TCR) genes into patient T cells is a promising approach for the treatment of both viral infections and cancer. Although efficient methods exist to identify antibodies for the treatment of these diseases, comparable strategies to identify TCRs have been lacking. We have developed a high-throughput DNA-based strategy to identify TCR sequences by the capture and sequencing of genomic DNA fragments encoding the TCR genes. We establish the value of this approach by assembling a large library of cancer germline tumor antigen-reactive TCRs. Furthermore, by exploiting the quantitative nature of TCR gene capture, we show the feasibility of identifying antigen-specific TCRs in oligoclonal T cell populations from either human material or TCR-humanized mice. Finally, we demonstrate the ability to identify tumor-reactive TCRs within intratumoral T cell subsets without knowledge of antigen specificities, which may be the first step toward the development of autologous TCR gene therapy to target patient-specific neoantigens in human cancer.

Original languageEnglish
Pages (from-to)1534-1541
Number of pages8
JournalNature Medicine
Volume19
Issue number11
DOIs
Publication statusPublished - Nov 2013
Externally publishedYes

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