Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma
- University Health Network, Canada
- University of Toronto, Canada
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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
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.
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.
Metrics
-
- 5,195
- views
-
- 940
- downloads
-
- 17
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma
eLife 9:e53244.
https://doi.org/10.7554/eLife.53244
Further reading
-
- Immunology and Inflammation
- Microbiology and Infectious Disease
The members of the Mycobacterium tuberculosis complex (MTBC) causing human tuberculosis comprise 10 phylogenetic lineages that differ in their geographical distribution. The human consequences of this phylogenetic diversity remain poorly understood. Here, we assessed the phenotypic properties at the host-pathogen interface of 14 clinical strains representing five major MTBC lineages. Using a human in vitro granuloma model combined with bacterial load assessment, microscopy, flow cytometry, and multiplexed-bead arrays, we observed considerable intra-lineage diversity. Yet, modern lineages were overall associated with increased growth rate and more pronounced granulomatous responses. MTBC lineages exhibited distinct propensities to accumulate triglyceride lipid droplets—a phenotype associated with dormancy—that was particularly pronounced in lineage 2 and reduced in lineage 3 strains. The most favorable granuloma responses were associated with strong CD4 and CD8 T cell activation as well as inflammatory responses mediated by CXCL9, granzyme B, and TNF. Both of which showed consistent negative correlation with bacterial proliferation across genetically distant MTBC strains of different lineages. Taken together, our data indicate that different virulence strategies and protective immune traits associate with MTBC genetic diversity at lineage and strain level.
-
- Immunology and Inflammation
Macrophages control intracellular pathogens like Salmonella by using two caspase enzymes at different times during infection.
