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Cell. 2018 Jan 25;172(3):549-563.e16. doi: 10.1016/j.cell.2017.11.043. Epub 2017 Dec 21.

Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes.

Author information

1
Program in Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
2
Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
3
Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
4
Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA.
5
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
6
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
7
Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
8
Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
9
Department of Bioengineering, Stanford University School of Medicine, Stanford, CA 94305, USA; Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
10
Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA; The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
11
Departments of Molecular and Cellular Physiology and Structural Biology, Stanford University School of Medicine, Stanford, CA 94305, USA; The Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: kcgarcia@stanford.edu.

Abstract

The immune system can mount T cell responses against tumors; however, the antigen specificities of tumor-infiltrating lymphocytes (TILs) are not well understood. We used yeast-display libraries of peptide-human leukocyte antigen (pHLA) to screen for antigens of "orphan" T cell receptors (TCRs) expressed on TILs from human colorectal adenocarcinoma. Four TIL-derived TCRs exhibited strong selection for peptides presented in a highly diverse pHLA-A02:01 library. Three of the TIL TCRs were specific for non-mutated self-antigens, two of which were present in separate patient tumors, and shared specificity for a non-mutated self-antigen derived from U2AF2. These results show that the exposed recognition surface of MHC-bound peptides accessible to the TCR contains sufficient structural information to enable the reconstruction of sequences of peptide targets for pathogenic TCRs of unknown specificity. This finding underscores the surprising specificity of TCRs for their cognate antigens and enables the facile indentification of tumor antigens through unbiased screening.

KEYWORDS:

T cell; T cell receptor; antigens; cancer; combinatorial biology; human leukocyte antigen; ligand identification; peptide library; peptides; single-cell sequencing

Comment in

PMID:
29275860
PMCID:
PMC5786495
[Available on 2019-01-25]
DOI:
10.1016/j.cell.2017.11.043
[Indexed for MEDLINE]

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