Back to Search Start Over

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

Authors :
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
Source :
Immunity [Immunity] 2021 Mar 09; Vol. 54 (3), pp. 586-602.e8.
Publication Year :
2021

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 <superscript>∗</superscript> 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.<br />Competing Interests: Declaration of interests C.L.M. is a founder of, holds equity in, and receives consulting fees from Lyell Immunopharma and receives consulting fees from NeoImmuneTech, Nektar, Apricity, and Roche. J.W.N. reports research support from Genentech/Roche, Merck, Novartis, Boehringer Ingelheim, Exelixis, Takeda Pharmaceuticals, Nektar Therapeutics, Adaptimmune, and GSK and has served in a consulting or advisory role for AstraZeneca, Genentech/Roche, Exelixis Inc., Jounce Therapeutics, Takeda Pharmaceuticals, Eli Lilly and Company, Calithera Biosciences, Amgen, Regeneron Pharmaceuticals, Natera, and Iovance Biotherapeutics. H.A.W. has received research support from Celgene, Clovis Oncology, Genentech/Roche, Arrys Therapeutics, Novartis, Merck, BMS, Exelixis, Lilly, Pfizer, and has participated on the advisory boards of Helsinn, Mirati, Cellworks, Genentech/Roche, Merck, and ITMIG. N.S.L. has received research funding from Intuitive Foundation and Auspex Diagnostics. E.S. is a consultant for Lyell Immunopharma. L.L. is a consultant for Lyell Immunopharma. S.A.F. is consulting for Lonza PerMed and Samsara BioCapital. M.D. reports research funding from Varian Medical Systems and Illumina; ownership interest in CiberMed and Foresight Diagnostics; patent filings related to cancer biomarkers; paid consultancy from Roche, AstraZeneca, BioNTech, Genentech, Novartis, and Gritstone Oncology; and travel/honoraria from Reflexion. K.C.G. is founder of 3T therapeutics. I.I.W. has received honoraria from Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, and MSD. I.I.W. is also supported by Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adaptive, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis, and Akoya. J.Z. reports grants from Merck and Johnson & Johnson, as well as adversary/consulting/Hornoraria fees from Bristol Myers Squibb, AstraZeneca, GenePlus, Innovent, OrigMed, and Roche outside the submitted work. This study was supported in part by a Cancer Prevention Research Institute of Texas Multi-Investigator Research Award (grant number RP160668) and the University of Texas Lung Specialized Programs of Research Excellence grant (grant number P50CA70907). S.-H.C., D.T., C.L.M., and M.M.D have a patent related to this work.<br /> (Copyright © 2021. Published by Elsevier Inc.)

Details

Language :
English
ISSN :
1097-4180
Volume :
54
Issue :
3
Database :
MEDLINE
Journal :
Immunity
Publication Type :
Academic Journal
Accession number :
33691136
Full Text :
https://doi.org/10.1016/j.immuni.2021.02.014