Abstract
To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A∗02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
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•The algorithm GLIPH2 enables analysis of shared TCR specificity and HLA prediction•Tumor-infiltrating T cells cross-react to EBV antigens and shared tumor antigens•EBV-specific T cells expanded in patients responding to immune checkpoint blockade•Cross-reactive CD8 T cells express GZMK
Chiou, Tseng, et al. analyze TCRβ chain sequences from 178 non-small cell lung cancer patients and identify shared specificity groups, which in turn enable antigen identification. One such antigenic epitope—a peptide from an epithelial protein—is cross-reactive to epitopes from Epstein-Barr virus and E. coli, suggesting that cross-reactivity may underlie the presence of pathogen-specific T cells in tumor infiltrates.