Journal
NPJ Precision Oncology
Authors
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 Hirst, Steven JM Jones, Janessa Laskin, Shahrad R Rassekh, Rebecca J Deyell, Marco A Marra

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.

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