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.
Highlights
Chordomas are malignant neoplasms derived from notochord cells typically originating in the spine, sacrum or base of the skull, affecting both adults and children
whole-genome and transcriptome analysis (WGTA) detected low somatic tumour mutation burden (TMB) for both cases (1.83 and 1.75 mutations per megabase for patients 1 and 2, respectively). Notable alterations in both cases included single copy losses affecting SMARCB1 (Fig. 1g), that were associated with low expression of SMARCB1 compared to both The Cancer Genome Atlas (TCGA) sarcoma[18] data set and a pan-cancer cohort of adult cancers, referred to as POG570, sequenced as part of the Personalized OncoGenomics (POG) programme[19] (Fig. 1h and Supplementary Table 1)
The beneficial response to the immune checkpoint inhibitor (ICI), nivolumab, in a paediatric chordoma we describe here support these initial observations, and add further support for antigendirected T cell responses and cytotoxic T cell infiltration that contribute to establishing an inflamed tumour microenvironment
Summary
Chordomas are malignant neoplasms derived from notochord cells typically originating in the spine, sacrum or base of the skull, affecting both adults and children. Differentiated chordomas (PDCs) are a recently recognized distinct subgroup of chordoma, which occurs predominantly in children, and is characterized by the expression of brachyury, an embryonic transcription factor encoded by the TBXT gene, and by loss of the SWI/SNF chromatin remodelling factor subunit, INI1, encoded by the SMARCB1 gene[1,2,3,4,5] These aggressive tumours are associated with a high risk of rapid local recurrence and distant metastasis and are generally poor candidates for primary resection, highlighting the need for effective systemic therapy. Broad response to ICIs among paediatric patients is lacking, growing evidence has shown responses to ICIs in tumours deficient in SWI/SNF chromatin remodelling genes, including but not limited to chordomas, rhabdoid tumours (RTs), and small cell carcinoma of the ovary hypercalcemic type tumours that affect paediatric and young adult populations[9,10,11,12,13,14,15]. The presence of infiltrating CD8+ T cells and expression of immune checkpoint genes in a subset of tumours is compatible with the notion that malignancies characterized by SWI/SNF deficiency may correlate with an immune hot phenotype and therapeutic response to ICIs10,11,13,14,16,17
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