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

Shin Heng Chiou, Diane Tseng, Alexandre Reuben, Vamsee Mallajosyula, Irene S. Molina, Stephanie Conley, Julie Wilhelmy, Alana M. McSween, Xinbo Yang, Daisuke Nishimiya, Rahul Sinha, Barzin Y. Nabet, Chunlin Wang, Joseph B. Shrager, Mark F. Berry, Leah Backhus, Natalie S. Lui, Heather A. Wakelee, Joel W. Neal, Sukhmani K. PaddaGerald J. Berry, Alberto Delaidelli, Poul H. Sorensen, Elena Sotillo, Patrick Tran, Jalen A. Benson, Rebecca Richards, Louai Labanieh, Dorota D. Klysz, David M. Louis, Steven A. Feldman, Maximilian Diehn, Irving L. Weissman, Jianjun Zhang, Ignacio I. Wistuba, P. Andrew Futreal, John V. Heymach, K. Christopher Garcia, Crystal L. Mackall, Mark M. Davis

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)586-602.e8
JournalImmunity
Volume54
Issue number3
DOIs
StatePublished - Mar 9 2021
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Keywords

  • EBV
  • EntS
  • GLIPH2
  • LMP2A
  • NSCLC
  • T cell receptor repertoire
  • T cell specificity
  • TCR
  • TMEM161A
  • cancer
  • cross-reactivity
  • tumor-infiltrating lymphocyte

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