Journal Article

DKFZ-2021-03225

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Clinical response to nivolumab in an INI1-deficient pediatric chordoma correlates with immunogenic recognition of brachyury.

Williamson, L. M. ; Rive, C. M. ; Di Francesco, D. ; Titmuss, E. ; Chun, H. E. ; Brown, S. D. ; Milne, K. ; Pleasance, E. ; Lee, A. F. ; Yip, S. ; Rosenbaum, D. G. ; Hasselblatt, M. ; Johann, P. D.DKFZ* ; Kool, M.DKFZ* ; Harvey, M. ; Dix, D. ; Renouf, D. J. ; Holt, R. A. ; Nelson, B. H. ; Hirst, M. ; Jones, S. J. M. ; Laskin, J. ; Rassekh, S. R. ; Deyell, R. J. ; Marra, M. A.

2021
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41698-021-00238-4

Abstract: 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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Contributing Institute(s):

1. B062 Pädiatrische Neuroonkologie (B062)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2021

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