Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury

Laura M. Williamson, Craig M. Rive, Daniela Di Francesco, Emma Titmuss, Hye Jung E. Chun, Scott D. Brown, Katy Milne, Erin Pleasance, Anna F. Lee, Stephen Yip, Daniel G. Rosenbaum, Martin Hasselblatt, Pascal D. Johann, Marcel Kool, Melissa Harvey, David Dix, Daniel J. Renouf, Robert A. Holt, Brad H. Nelson, Martin HirstSteven J.M. Jones, Janessa Laskin, Shahrad R. Rassekh, Rebecca J. Deyell, Marco A. Marra

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16 Citations (Scopus)


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.

Original languageEnglish
Article number103
JournalNPJ Precision Oncology
Issue number1
Publication statusPublished - Dec 2021


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