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Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury
Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688516/ https://www.ncbi.nlm.nih.gov/pubmed/34931022 http://dx.doi.org/10.1038/s41698-021-00238-4 |
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author | Williamson, Laura M. Rive, Craig M. Di Francesco, Daniela Titmuss, Emma Chun, Hye-Jung E. Brown, Scott D. Milne, Katy Pleasance, Erin Lee, Anna F. Yip, Stephen Rosenbaum, Daniel G. Hasselblatt, Martin Johann, Pascal D. Kool, Marcel Harvey, Melissa Dix, David Renouf, Daniel J. Holt, Robert A. Nelson, Brad H. Hirst, Martin Jones, Steven J. M. Laskin, Janessa Rassekh, Shahrad R. Deyell, Rebecca J. Marra, Marco A. |
author_facet | Williamson, Laura M. Rive, Craig M. Di Francesco, Daniela Titmuss, Emma Chun, Hye-Jung E. Brown, Scott D. Milne, Katy Pleasance, Erin Lee, Anna F. Yip, Stephen Rosenbaum, Daniel G. Hasselblatt, Martin Johann, Pascal D. Kool, Marcel Harvey, Melissa Dix, David Renouf, Daniel J. Holt, Robert A. Nelson, Brad H. Hirst, Martin Jones, Steven J. M. Laskin, Janessa Rassekh, Shahrad R. Deyell, Rebecca J. Marra, Marco A. |
author_sort | Williamson, Laura M. |
collection | PubMed |
description | Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide–MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers. |
format | Online Article Text |
id | pubmed-8688516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-86885162022-01-04 Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury Williamson, Laura M. Rive, Craig M. Di Francesco, Daniela Titmuss, Emma Chun, Hye-Jung E. Brown, Scott D. Milne, Katy Pleasance, Erin Lee, Anna F. Yip, Stephen Rosenbaum, Daniel G. Hasselblatt, Martin Johann, Pascal D. Kool, Marcel Harvey, Melissa Dix, David Renouf, Daniel J. Holt, Robert A. Nelson, Brad H. Hirst, Martin Jones, Steven J. M. Laskin, Janessa Rassekh, Shahrad R. Deyell, Rebecca J. Marra, Marco A. NPJ Precis Oncol Case Report Poorly differentiated chordoma (PDC) is a recently recognized subtype of chordoma characterized by expression of the embryonic transcription factor, brachyury, and loss of INI1. PDC primarily affects children and is associated with a poor prognosis and limited treatment options. Here we describe the molecular and immune tumour microenvironment profiles of two paediatric PDCs produced using whole-genome, transcriptome and whole-genome bisulfite sequencing (WGBS) and multiplex immunohistochemistry. Our analyses revealed the presence of tumour-associated immune cells, including CD8+ T cells, and expression of the immune checkpoint protein, PD-L1, in both patient samples. Molecular profiling provided the rationale for immune checkpoint inhibitor (ICI) therapy, which resulted in a clinical and radiographic response. A dominant T cell receptor (TCR) clone specific for a brachyury peptide–MHC complex was identified from bulk RNA sequencing, suggesting that targeting of the brachyury tumour antigen by tumour-associated T cells may underlie this clinical response to ICI. Correlative analysis with rhabdoid tumours, another INI1-deficient paediatric malignancy, suggests that a subset of tumours may share common immune phenotypes, indicating the potential for a therapeutically targetable subgroup of challenging paediatric cancers. Nature Publishing Group UK 2021-12-20 /pmc/articles/PMC8688516/ /pubmed/34931022 http://dx.doi.org/10.1038/s41698-021-00238-4 Text en © Crown 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Case Report Williamson, Laura M. Rive, Craig M. Di Francesco, Daniela Titmuss, Emma Chun, Hye-Jung E. Brown, Scott D. Milne, Katy Pleasance, Erin Lee, Anna F. Yip, Stephen Rosenbaum, Daniel G. Hasselblatt, Martin Johann, Pascal D. Kool, Marcel Harvey, Melissa Dix, David Renouf, Daniel J. Holt, Robert A. Nelson, Brad H. Hirst, Martin Jones, Steven J. M. Laskin, Janessa Rassekh, Shahrad R. Deyell, Rebecca J. Marra, Marco A. Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
title | Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
title_full | Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
title_fullStr | Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
title_full_unstemmed | Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
title_short | Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
title_sort | clinical response to nivolumab in an ini1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury |
topic | Case Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8688516/ https://www.ncbi.nlm.nih.gov/pubmed/34931022 http://dx.doi.org/10.1038/s41698-021-00238-4 |
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