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

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) expre...

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Bibliographic Details
Published in:	Cell 2018-01, Vol.172 (3), p.549-563.e16
Main Authors:	Gee, Marvin H., Han, Arnold, Lofgren, Shane M., Beausang, John F., Mendoza, Juan L., Birnbaum, Michael E., Bethune, Michael T., Fischer, Suzanne, Yang, Xinbo, Gomez-Eerland, Raquel, Bingham, David B., Sibener, Leah V., Fernandes, Ricardo A., Velasco, Andrew, Baltimore, David, Schumacher, Ton N., Khatri, Purvesh, Quake, Stephen R., Davis, Mark M., Garcia, K. Christopher
Format:	Article
Language:	eng
Subjects:	Adenocarcinoma - immunology Aged Animals antigens Antigens, Neoplasm - chemistry Antigens, Neoplasm - immunology cancer Cell Line, Tumor Cells, Cultured Colorectal Neoplasms - immunology combinatorial biology HEK293 Cells HLA-A Antigens - chemistry HLA-A Antigens - immunology human leukocyte antigen Humans ligand identification Lymphocytes, Tumor-Infiltrating - immunology Male Middle Aged Peptide Library peptides Receptors, Antigen, T-Cell - immunology Sf9 Cells single-cell sequencing Spodoptera T cell T cell receptor
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Summary:	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-A∗02:01 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. [Display omitted] •Development of a human leukocyte antigen library for TCR ligand identification•Single-cell sequencing and phenotyping of T cells infiltrating human colon cancer•Ligand discovery for four tumor-derived T cell receptors•Identification of a shared non-mutated tumor antigen between two patients A new approach for identifying T cell receptor ligands reveals insights into the specificity of tumor-infiltrating lymphocytes.
ISSN:	0092-8674 1097-4172