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

Official URL:https://doi.org/10.1038/nm.3359
PubMed:View item in PubMed
Creators Name:Linnemann, C. and Heemskerk, B. and Kvistborg, P. and Kluin, R.J.C. and Bolotin, D.A. and Chen, X. and Bresser, K. and Nieuwland, M. and Schotte, R. and Michels, S. and Gomez-Eerland, R. and Jahn, L. and Hombrink, P. and Legrand, N. and Shu, C.J. and Mamedov, I.Z. and Velds, A. and Blank, C.U. and Haanen, J.B.A.G. and Turchaninova, M.A. and Kerkhoven, R.M. and Spits, H. and Hadrup, S.R. and Heemskerk, M.H.M. and Blankenstein, T. and Chudakov, D.M. and Bendle, G.M. and Schumacher, T.N.M.
Journal Title:Nature Medicine
Journal Abbreviation:Nat Med
Volume:19
Number:11
Page Range:1534-1541
Date:November 2013
Keywords:Gene Library, Genetic Therapy, High-Throughput Nucleotide Sequencing, Neoplasm Antigens, Neoplasms, T-Cell Antigen Receptors, T-Cell Receptor Genes, T-Lymphocytes, Animals, Mice
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.
ISSN:1078-8956
Publisher:Nature Publishing Group (U.S.A.)
Item Type:Article

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