Journal
NPJ PRECISION ONCOLOGY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41698-021-00238-4
Keywords
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Funding
- BC Cancer
- BC Children's Hospital Foundations
- Genome British Columbia [B20POG]
- Genome BC [202SEQ, 212SEQ, 12002]
- Canada Foundation for Innovation [20070, 30981, 30198, 33408, 36239]
- Canada's Networks of Centres of Excellence (BioCanRx)
- BC Knowledge Development Fund
- Canadian Institutes of Health Research (CIHR)
- Genome BC, Canadian Epigenetics, Epigenomics, Environment and Health Research Consortium (CEEHRC) initiative [142875]
- Canadian Institutes of Health Research Foundation [FDN 143288]
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Poorly differentiated chordoma (PDC) primarily affects children with a poor prognosis and limited treatment options. Molecular analysis revealed the presence of tumor-associated immune cells and the expression of immune checkpoint proteins, providing a rationale for immune checkpoint inhibitor therapy. Targeting the brachyury tumor antigen by tumor-associated T cells may underlie the clinical response to immune checkpoint inhibitors.
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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