CHROMOSOMAL instability in oesophageal adenocarcinoma is closely associated with tumour driven immunosuppression and adverse clinical outcomes, providing new insight into how genomic disruption reshapes immune signalling in this disease.
Chromosomal Instability and Immune Signalling
Chromosomal instability is a defining feature of oesophageal adenocarcinoma and contributes to tumour aggressiveness and metastatic progression. It is also known to activate the cyclic GMP AMP synthase stimulator of interferon genes pathway, which is typically linked to antitumour immunity. However, despite a high burden of chromosomal instability, this pathway remains largely intact in these tumours.
To address this paradox, investigators analysed multiple oesophageal cancer models and identified myeloid attracting chemokines as conserved targets of chromosomal instability. Among these, CXCL8 emerged as a key mediator, indicating that chromosomal instability may redirect immune signalling towards tumour promoting inflammation rather than effective immune defence.
Measuring Chromosomal Instability in Tumours
To characterise this process in human disease, researchers quantified ongoing chromosomal instability by measuring cyclic GMP AMP synthase positive micronuclei using multiplexed immunofluorescence microscopy. These findings were validated through whole genome sequencing, confirming the robustness of this approach.
By integrating in situ detection of chromosomal instability with single nucleus RNA sequencing and multiplex immunophenotyping, the study linked chromosomal instability with tumour intrinsic innate immune activation and increased CXCL8 expression. This comprehensive analysis enabled a detailed understanding of how chromosomal instability influences the tumour microenvironment.
Clinical Impact of Chromosomal Instability
Tumours with high levels of chromosomal instability were characterised by myeloid cell dominance and immunosuppressive features. In patients with oesophageal adenocarcinoma, these tumours correlated with poor outcomes and aberrant signalling through the cyclic GMP AMP synthase stimulator of interferon genes pathway.
These findings provide an explanation for the persistence of this pathway despite extensive genomic instability and suggest that chromosomal instability driven inflammation may promote immune evasion.
Overall, the data highlight disruption of the chromosomal instability cyclic GMP AMP synthase inflammation axis as a potential therapeutic strategy, with the aim of restoring effective immune responses and improving outcomes in oesophageal adenocarcinoma.
Reference
Beernaert B et al. Chromosomal instability shapes the tumor microenvironment of esophageal adenocarcinoma via a cGAS–chemokine–myeloid axis. bioRxiv; 2025 May:2025.05.06.652454.
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