1. Immunology and Inflammation
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Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma

Research Article
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Cite this article as: eLife 2020;9:e53244 doi: 10.7554/eLife.53244

Abstract

HLA-restricted T cell responses can induce antitumor effects in cancer patients. Previous human T cell research has largely focused on the few HLA alleles prevalent in a subset of ethnic groups. Here, using a panel of newly developed peptide-exchangeable peptide/HLA multimers and artificial antigen-presenting cells for 25 different class I alleles and greater than 800 peptides, we systematically and comprehensively mapped shared antigenic epitopes recognized by tumor-infiltrating T lymphocytes (TILs) from eight melanoma patients for all their class I alleles. We were able to determine the specificity, on average, of 12.2% of the TILs recognizing a mean of 3.1 shared antigen-derived epitopes across HLA-A, B, and C. Furthermore, we isolated a number of cognate T cell receptor genes with tumor reactivity. Our novel strategy allows for a more complete examination of the immune response and development of novel cancer immunotherapy not limited by HLA allele prevalence or tumor mutation burden.

Article and author information

Author details

  1. Kenji Murata

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    Kenji Murata, The University Health Network has filed patent application related to this study on which Kenji Murata is named as an inventor (US16/095,913, US62/813,639, US62/813,642, US62/813,644, US62/813,645, US62/813,647, US62/813,650, US62/813,651, and US62/823,487)..
  2. Munehide Nakatsugawa

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    Munehide Nakatsugawa, The University Health Network has filed patent application related to this study on which Munehide Nakatsugawa is named as an inventor (US16/095,913)..
  3. Muhammed A Rahman

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    Muhammed A Rahman, The University Health Network has filed patent application related to this study on which Muhammed A. Rahman is named as an inventor (US16/095,913)..
  4. Linh T Nguyen

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  5. Douglas G Millar

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  6. David Thomas Mulder

    Clinical Cancer Genomics, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  7. Kenji Sugata

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  8. Hiroshi Saijo

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  9. Yukiko Matsunaga

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  10. Yuki Kagoya

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  11. Tingxi Guo

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  12. Mark Anczurowski

    Department of Immunology, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  13. Chung-Hsi Wang

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  14. Brian D Burt

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  15. Dalam Ly

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  16. Kayoko Saso

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    Kayoko Saso, The University Health Network has filed patent application related to this study on which Kayoko Saso is named as an inventor (US62/813,639, US62/813,642, US62/813,644, US62/813,645, US62/813,647, US62/813,650, US62/813,651, and US62/823,487)..
  17. Alexandra Easson

    Surgical Oncology, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  18. David P Goldstein

    Surgical Oncology, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  19. Michael Reedijk

    Surgical Oncology, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  20. Danny A Ghazarian

    Laboratory Medicine and Pathobiology, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  21. Trevor J Pugh

    Medical Biophysics, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  22. Marcus O Butler

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    Marcus O Butler, Marcus O. Butler has served on advisory boards for Merck, BMS, Novartis, GSK, Immunocore, immunovaccine, Sanofi, and EMD Serono and received research funding for investigator initiated clinical trials from Merck and Takara Bio..
  23. Tak W Mak

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  24. Pamela S Ohashi

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    Competing interests
    No competing interests declared.
  25. Naoto Hirano

    Princess Margaret Cancer Centre, University Health Network, Toronto, Canada
    For correspondence
    naoto.hirano@uhnresearch.ca
    Competing interests
    Naoto Hirano, Naoto Hirano reports receiving a research grant from and is a consultant for Takara Bio and Otsuka Pharmaceutical and serving on an advisory board for F. Hoffmann-La Roche. The University Health Network has filed patent application related to this study on which Naoto Hirano is named as an inventor (US16/095,913, US62/813,639, US62/813,642, US62/813,644, US62/813,645, US62/813,647, US62/813,650, US62/813,651, and US62/823,487)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9070-4754

Funding

Ontario Institute for Cancer Research (Clinical Investigator Award,IA-039)

  • Naoto Hirano

Province of Ontario

  • Mark Anczurowski

Natural Sciences and Engineering Research Council of Canada (Postgraduate Scholarship)

  • Tingxi Guo

Terry Fox Research Institute (Immunotherapy NeTwork (iTNT) Program)

  • Naoto Hirano

Terry Fox Research Institute (Immunotherapy NeTwork (iTNT) Program)

  • Pamela S Ohashi

Princess Margaret Cancer Centre Innovattion Accelerator Fund

  • Naoto Hirano

Princess Margaret Cancer Foundation

  • Naoto Hirano

Princess Margaret Cancer Foundation

  • Marcus O Butler

Mitacs (Intership)

  • Kenji Murata

Japan Society for the Promotion of Science (Postdoctoral Fellowship for Overseas Researchers and a Guglietti Fellowship)

  • Yuki Kagoya

Province of Ontario

  • Tingxi Guo

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This study was conducted in accordance with the Helsinki Declaration and approved by the Research Ethics Board of the University Health Network, Toronto, Canada (UHN REB# 11-0343, 11-0348). Written informed consent was obtained from all healthy donors who provided peripheral blood samples.

Reviewing Editor

  1. Guido Kroemer, University of Paris Descartes, France

Publication history

  1. Received: November 1, 2019
  2. Accepted: April 4, 2020
  3. Accepted Manuscript published: April 21, 2020 (version 1)
  4. Version of Record published: May 18, 2020 (version 2)

Copyright

© 2020, Murata et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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