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

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.

Coexpression of HHLA2 and PD-L1 on Tumor Cells Independently Predicts the Survival of Spinal Chordoma Patients

“…In chordoma, studies have demonstrated frequent immune cell infiltration in the tumor microenvironment and their significant association with patient characteristics and prognosis (18). Although these data suggest immunotherapy as a promising therapeutic strategy for chordoma, the results are still controversial, and data regarding the efficacy of immune checkpoint blockades in this disease are limited (19)(20)(21)(22). Moreover, previous studies demonstrated that only 13-45% of solid cancer patients had a good response to immunotherapy, indicating alternative immunosuppressive checkpoints or pathways disrupting immunosurveillance (23,24).…”

Metastatic skull base chordoma: A systematic review

“… 61 , 62 The prognosis for poorly differentiated chordomas (PDC), characterized by the expression of brachyury and loss INI1, is significantly worse compared with their conventional counterparts, and treatment options for this condition are sparse. 63 While there has been a recent clinical trial has investigated the role of Tazemetostat in treating adolescents and adults with PDC, the majority of patients with this condition are typically pediatric. 64 Although there have been other trials investigating other target treatment molecules including nivolumab, these studies were limited by small samples.…”

“… 64 Although there have been other trials investigating other target treatment molecules including nivolumab, these studies were limited by small samples. 63 Additional research on molecular markers, genomic aberrancies, and molecular targeted therapies are needed in the treatment of PDCs. However, the ability to conduct trials on prognostic biomarkers and new therapeutic agents may be challenging due to the rarity of this disease.…”

“…Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, has demonstrated promising results when used in conjunction with erlotinib therapy, as VEGF levels have been found to be substantially in chordoma tissues 61,62 . The prognosis for poorly differentiated chordomas (PDC), characterized by the expression of brachyury and loss INI1, is significantly worse compared with their conventional counterparts, and treatment options for this condition are sparse 63 . While there has been a recent clinical trial has investigated the role of Tazemetostat in treating adolescents and adults with PDC, the majority of patients with this condition are typically pediatric 64 .…”

Research hotspots and trends of chordoma: A bibliometric analysis

“…Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) are highly expressed in chordoma (70)(71)(72). Nivolumab, an anti-PD-1 monoclonal antibody, showed effectivity against chordoma in vivo and is currently evaluated in clinical trials for chordomas (73,74). In addition, avelumab could inhibit the chordoma cell proliferation by targeting PD-L1, while further clinical evidence is still needed for chordoma (75).…”