Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRb 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.

Automated summary

Through analyzing a large number of T cell receptor sequences, we identified T cell receptors with shared antigen specificity in a subset of non-small cell lung cancer patients and identified some specificity groups enriched in tumors. Using a yeast peptide-HLA display library, we confirmed the antigenic epitopes of one tumor-enriched specificity group, indicating that pathogen cross-reactivity may be a feature of multiple cancers.