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 Padda; Gerald 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

doi:10.1016/j.immuni.2021.02.014

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. doi: 10.1016/j.immuni.2021.02.014.

Authors

Shin-Heng Chiou¹, Diane Tseng², Alexandre Reuben³, Vamsee Mallajosyula¹, Irene S Molina⁴, Stephanie Conley⁵, Julie Wilhelmy⁶, Alana M McSween¹, Xinbo Yang⁷, Daisuke Nishimiya⁷, Rahul Sinha⁵, Barzin Y Nabet⁸, Chunlin Wang¹, Joseph B Shrager⁹, Mark F Berry¹⁰, Leah Backhus⁹, Natalie S Lui⁹, Heather A Wakelee¹¹, Joel W Neal¹¹, Sukhmani K Padda², Gerald J Berry¹², Alberto Delaidelli¹³, Poul H Sorensen¹³, Elena Sotillo¹⁴, Patrick Tran¹⁴, Jalen A Benson¹⁰, Rebecca Richards¹⁵, Louai Labanieh¹⁶, Dorota D Klysz¹⁴, David M Louis¹, Steven A Feldman¹⁴, Maximilian Diehn¹⁷, Irving L Weissman⁵, Jianjun Zhang¹⁸, Ignacio I Wistuba¹⁹, P Andrew Futreal²⁰, John V Heymach³, K Christopher Garcia²¹, Crystal L Mackall²², Mark M Davis²³

Affiliations

¹ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA.
² Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA.
³ Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Rutgers Cancer Institute of New Jersey, Robert Wood Johnson Medical School, Rutgers, The State University of New Jersey, New Brunswick, NJ 08901, USA.
⁵ Institute for Stem Cell Biology and Regenerative Medicine Institute, Stanford University, Stanford, CA 94305, USA.
⁶ Stanford Genome Technology Center, Stanford University, Stanford, CA 94305, USA.
⁷ Department of Molecular and Cellular Physiology and Structural Biology, Stanford University, Stanford, CA 94305, USA.
⁸ Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA.
⁹ Department of Cardiothoracic Surgery - Thoracic Surgery, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford, CA 94305, USA.
¹⁰ Department of Cardiothoracic Surgery - Thoracic Surgery, Stanford University, Stanford, CA 94305, USA.
¹¹ Department of Medicine, Division of Oncology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford, CA 94305, USA.
¹² Department of Pathology, Stanford University, Stanford, CA 94305, USA.
¹³ Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada.
¹⁴ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA.
¹⁵ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA.
¹⁶ Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
¹⁷ Institute for Stem Cell Biology and Regenerative Medicine Institute, Stanford University, Stanford, CA 94305, USA; Department of Radiation Oncology, Stanford University, Stanford, CA 94305, USA; Stanford Cancer Institute, Stanford, CA 94305, USA.
¹⁸ Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Genomic Medicine, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
¹⁹ Department of Translational Molecular Pathology, Division of Pathology and Laboratory Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
²⁰ Department of Genomic Medicine, Division of Cancer Medicine, MD Anderson Cancer Center, Houston, TX 77030, USA.
²¹ Department of Molecular and Cellular Physiology and Structural Biology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
²² Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University, Stanford, CA 94305, USA; Department of Pediatrics, Stanford University, Stanford, CA 94305, USA; Department of Medicine, Stanford University, Stanford, CA 94305, USA.
²³ Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA. Electronic address: mmdavis@stanford.edu.

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.

Keywords: EBV; EntS; GLIPH2; LMP2A; NSCLC; T cell receptor repertoire; T cell specificity; TCR; TMEM161A; cancer; cross-reactivity; tumor-infiltrating lymphocyte.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Algorithms
Antigen Presentation
Antigens, Neoplasm / metabolism
Carcinoma, Non-Small-Cell Lung / immunology*
Cells, Cultured
Cross Reactions
Epitope Mapping / methods*
Epitopes, T-Lymphocyte / genetics*
Epitopes, T-Lymphocyte / metabolism
HLA-A2 Antigen / metabolism
Humans
Lung Neoplasms / immunology*
Protein Binding
Receptors, Antigen, T-Cell, alpha-beta / genetics*
T-Cell Antigen Receptor Specificity
T-Lymphocytes / immunology*

Substances

Antigens, Neoplasm
Epitopes, T-Lymphocyte
HLA-A*02:01 antigen
HLA-A2 Antigen
Receptors, Antigen, T-Cell, alpha-beta

Abstract

Publication types

MeSH terms

Substances

Grants and funding