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Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.
Chiou SH, Tseng D, Reuben A, Mallajosyula V, Molina IS, Conley S, Wilhelmy J, McSween AM, Yang X, Nishimiya D, Sinha R, Nabet BY, Wang C, Shrager JB, Berry MF, Backhus L, Lui NS, Wakelee HA, Neal JW, Padda SK, Berry GJ, Delaidelli A, Sorensen PH, Sotillo E, Tran P, Benson JA, Richards R, Labanieh L, Klysz DD, Louis DM, Feldman SA, Diehn M, Weissman IL, Zhang J, Wistuba II, Futreal PA, Heymach JV, Garcia KC, Mackall CL, Davis MM. Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery. Immunity. 2021 Mar 9; 54(3):586-602.e8.
To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCR 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 A02:01 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.