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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Published in | Cell Vol. 172; no. 3; pp. 549 - 563.e16 |
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Main Authors | , , , , , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
25.01.2018
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Subjects | |
Online Access | Get full text |
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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.
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•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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2017.11.043 |