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...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:NPJ precision oncology 2021-12, Vol.5 (1), p.103-103, Article 103
Hauptverfasser: 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.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:2397-768X
2397-768X
DOI:10.1038/s41698-021-00238-4