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. Turchaninova; Ron M. Kerkhoven; Hergen Spits; Sine Reker Hadrup; Mirjam H. M. Heemskerk; Thomas Blankenstein; Dmitriy M. Chudakov; Gavin M. Bendle; Ton N. M. Schumacher

doi:10.1038/nm.3359

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 journal › Journal article › Research › peer-review

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 language	English
Journal	Nature Medicine
Volume	19
Issue number	11
Pages (from-to)	1534-1541
ISSN	1078-8956
DOIs	https://doi.org/10.1038/nm.3359
Publication status	Published - 2013
Externally published	Yes

Keywords

Biochemistry, Genetics and Molecular Biology (all)
Medicine (all)
gamma interferon
genomic DNA
T lymphocyte receptor alpha chain
T lymphocyte receptor beta chain
amino acid sequence
animal experiment
antigen specificity
article
controlled study
cytokine production
gene locus
gene therapy
gene transfer
high throughput sequencing
human
human cell
lymphocyte subpopulation
mouse
nonhuman
priority journal
protein analysis
T lymphocyte receptor gene
T lymphocyte subpopulation
Animals
Antigens, Neoplasm
Gene Library
Genes, T-Cell Receptor
Genetic Therapy
High-Throughput Nucleotide Sequencing
Humans
Mice
Neoplasms
Receptors, Antigen, T-Cell
T-Lymphocytes
Mus
Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common
Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] mouse common
human TCR gene [Hominidae] human T cell receptor gene expression
antigen-specific T cell receptor antigen-specific TCR
genomic DNA fragments
T cell receptor TCR
02506, Cytology - Animal
02508, Cytology - Human
03502, Genetics - General
03506, Genetics - Animal
03508, Genetics - Human
15002, Blood - Blood and lymph studies
15004, Blood - Blood cell studies
34502, Immunology - General and methods
34508, Immunology - Immunopathology, tissue immunology
Immune System
Methods and Techniques
Molecular Genetics
autoimmune disease Autoimmune Diseases (MeSH) immune system disease
Biochemistry and Molecular Biophysics
Chemical Coordination and Homeostasis
T cell immune system, blood and lymphatics
high-throughput DNA-based method laboratory techniques, genetic techniques
BIOCHEMISTRY
CELL
MEDICINE,
T-CELL-RECEPTORS
CANCER REGRESSION
MONOCLONAL-ANTIBODIES
ADOPTIVE TRANSFER
MELANOMA PATIENTS
IMMUNE-SYSTEM
IN-VIVO
LYMPHOCYTES
THERAPY
MICE
HIGH throughput screening (Drug development)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nm.3359

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Cite this

Linnemann, C., Heemskerk, B., Kvistborg, P., Kluin, R. J. C., Bolotin, D. A., Chen, X., Bresser, K., Nieuwland, M., Schotte, R., Michels, S., Gomez-Eerland, R., Jahn, L., Hombrink, P., Legrand, N., Shu, C. J., Mamedov, I. Z., Velds, A., Blank, C. U., Haanen, J. B. A. G., ... Schumacher, T. N. M. (2013). High-throughput identification of antigen-specific TCRs by TCR gene capture. Nature Medicine, 19(11), 1534-1541. https://doi.org/10.1038/nm.3359

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title = "High-throughput identification of antigen-specific TCRs by TCR gene capture",

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.",

keywords = "Biochemistry, Genetics and Molecular Biology (all), Medicine (all), gamma interferon, genomic DNA, T lymphocyte receptor alpha chain, T lymphocyte receptor beta chain, amino acid sequence, animal experiment, antigen specificity, article, controlled study, cytokine production, gene locus, gene therapy, gene transfer, high throughput sequencing, human, human cell, lymphocyte subpopulation, mouse, nonhuman, priority journal, protein analysis, T lymphocyte receptor gene, T lymphocyte subpopulation, Animals, Antigens, Neoplasm, Gene Library, Genes, T-Cell Receptor, Genetic Therapy, High-Throughput Nucleotide Sequencing, Humans, Mice, Neoplasms, Receptors, Antigen, T-Cell, T-Lymphocytes, Mus, Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common, Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] mouse common, human TCR gene [Hominidae] human T cell receptor gene expression, antigen-specific T cell receptor antigen-specific TCR, genomic DNA fragments, T cell receptor TCR, 02506, Cytology - Animal, 02508, Cytology - Human, 03502, Genetics - General, 03506, Genetics - Animal, 03508, Genetics - Human, 15002, Blood - Blood and lymph studies, 15004, Blood - Blood cell studies, 34502, Immunology - General and methods, 34508, Immunology - Immunopathology, tissue immunology, Immune System, Methods and Techniques, Molecular Genetics, autoimmune disease Autoimmune Diseases (MeSH) immune system disease, Biochemistry and Molecular Biophysics, Chemical Coordination and Homeostasis, T cell immune system, blood and lymphatics, high-throughput DNA-based method laboratory techniques, genetic techniques, BIOCHEMISTRY, CELL, MEDICINE,, T-CELL-RECEPTORS, CANCER REGRESSION, MONOCLONAL-ANTIBODIES, ADOPTIVE TRANSFER, MELANOMA PATIENTS, IMMUNE-SYSTEM, IN-VIVO, LYMPHOCYTES, THERAPY, MICE, HIGH throughput screening (Drug development)",

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

year = "2013",

doi = "10.1038/nm.3359",

language = "English",

volume = "19",

pages = "1534--1541",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "11",

}

Linnemann, C, Heemskerk, B, Kvistborg, P, Kluin, RJC, Bolotin, DA, Chen, X, Bresser, K, Nieuwland, M, Schotte, R, Michels, S, Gomez-Eerland, R, Jahn, L, Hombrink, P, Legrand, N, Shu, CJ, Mamedov, IZ, Velds, A, Blank, CU, Haanen, JBAG, Turchaninova, MA, Kerkhoven, RM, Spits, H, Hadrup, SR, Heemskerk, MHM, Blankenstein, T, Chudakov, DM, Bendle, GM & Schumacher, TNM 2013, 'High-throughput identification of antigen-specific TCRs by TCR gene capture', Nature Medicine, vol. 19, no. 11, pp. 1534-1541. https://doi.org/10.1038/nm.3359

TY - JOUR

T1 - High-throughput identification of antigen-specific TCRs by TCR gene capture

AU - Linnemann, Carsten

AU - Heemskerk, Bianca

AU - Kvistborg, Pia

AU - Kluin, Roelof J. C.

AU - Bolotin, Dmitriy A.

AU - Chen, Xiaojing

AU - Bresser, Kaspar

AU - Nieuwland, Marja

AU - Schotte, Remko

AU - Michels, Samira

AU - Gomez-Eerland, Raquel

AU - Jahn, Lorenz

AU - Hombrink, Pleun

AU - Legrand, Nicolas

AU - Shu, Chengyi Jenny

AU - Mamedov, Ilgar Z.

AU - Velds, Arno

AU - Blank, Christian U.

AU - Haanen, John B. A. G.

AU - Turchaninova, Maria A.

AU - Kerkhoven, Ron M.

AU - Spits, Hergen

AU - Hadrup, Sine Reker

AU - Heemskerk, Mirjam H. M.

AU - Blankenstein, Thomas

AU - Chudakov, Dmitriy M.

AU - Bendle, Gavin M.

AU - Schumacher, Ton N. M.

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

KW - Biochemistry, Genetics and Molecular Biology (all)

KW - Medicine (all)

KW - gamma interferon

KW - genomic DNA

KW - T lymphocyte receptor alpha chain

KW - T lymphocyte receptor beta chain

KW - amino acid sequence

KW - animal experiment

KW - antigen specificity

KW - article

KW - controlled study

KW - cytokine production

KW - gene locus

KW - gene therapy

KW - gene transfer

KW - high throughput sequencing

KW - human

KW - human cell

KW - lymphocyte subpopulation

KW - mouse

KW - nonhuman

KW - priority journal

KW - protein analysis

KW - T lymphocyte receptor gene

KW - T lymphocyte subpopulation

KW - Animals

KW - Antigens, Neoplasm

KW - Gene Library

KW - Genes, T-Cell Receptor

KW - Genetic Therapy

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Mice

KW - Neoplasms

KW - Receptors, Antigen, T-Cell

KW - T-Lymphocytes

KW - Mus

KW - Primates Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Humans, Mammals, Primates, Vertebrates) - Hominidae [86215] human common

KW - Rodentia Mammalia Vertebrata Chordata Animalia (Animals, Chordates, Mammals, Nonhuman Vertebrates, Nonhuman Mammals, Rodents, Vertebrates) - Muridae [86375] mouse common

KW - human TCR gene [Hominidae] human T cell receptor gene expression

KW - antigen-specific T cell receptor antigen-specific TCR

KW - genomic DNA fragments

KW - T cell receptor TCR

KW - 02506, Cytology - Animal

KW - 02508, Cytology - Human

KW - 03502, Genetics - General

KW - 03506, Genetics - Animal

KW - 03508, Genetics - Human

KW - 15002, Blood - Blood and lymph studies

KW - 15004, Blood - Blood cell studies

KW - 34502, Immunology - General and methods

KW - 34508, Immunology - Immunopathology, tissue immunology

KW - Immune System

KW - Methods and Techniques

KW - Molecular Genetics

KW - autoimmune disease Autoimmune Diseases (MeSH) immune system disease

KW - Biochemistry and Molecular Biophysics

KW - Chemical Coordination and Homeostasis

KW - T cell immune system, blood and lymphatics

KW - high-throughput DNA-based method laboratory techniques, genetic techniques

KW - BIOCHEMISTRY

KW - CELL

KW - MEDICINE,

KW - T-CELL-RECEPTORS

KW - CANCER REGRESSION

KW - MONOCLONAL-ANTIBODIES

KW - ADOPTIVE TRANSFER

KW - MELANOMA PATIENTS

KW - IMMUNE-SYSTEM

KW - IN-VIVO

KW - LYMPHOCYTES

KW - THERAPY

KW - MICE

KW - HIGH throughput screening (Drug development)

U2 - 10.1038/nm.3359

DO - 10.1038/nm.3359

M3 - Journal article

C2 - 24121928

SN - 1078-8956

VL - 19

SP - 1534

EP - 1541

JO - Nature Medicine

JF - Nature Medicine

IS - 11

ER -

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

Abstract

Keywords

UN SDGs

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