Immune checkpoint inhibitor response in sarcomas associates with immune infiltrates and increased expression of transposable elements and viral response pathways
Nacev, B. A.; Bradic, M.; Woo, H. J.; Richards, A. L.; Kelly, C. M.; Dickson, M. A.; Gounder, M. M.; Keohan, M. L.; Chi, P.; Movva, S.; Maki, R.; Slotkin, E. K.; Rosenbaum, E.; Avutu, V.; Chan, J. E.; Banks, L.; Adamson, T.; Singer, S.; Antonescu, C. R.; Tap, W. D.; Donoghue, M. T.; D'Angelo, S. P.
Show abstract
Response to immune checkpoint inhibition (ICI) in sarcoma is overall low and heterogeneous. Understanding determinants of ICI outcomes may improve efficacy and patient selection. One potential mechanism is epigenetic de-repression of transposable elements (TEs), which stimulates antitumor immunity. Here, we used transcriptomic data to assign immune-hot versus immune-cold status to 67 pre-treatment biopsies of sarcomas from patients treated on ICI trials. Progression-free survival and overall response was superior in the immune-hot group. Expression of TEs and epigenetic regulators significantly predicted immune-hot status in a regression model in which specific TE subfamilies and IKZF1, a chromatin-interacting transcription factor, were significantly contributory. TE and IKZF1 expression positively correlated with tumor immune infiltrates, inflammatory pathways, and clinical outcomes. Key findings were confirmed in a validation cohort (n=190). This work suggests that TE and IKZF1 expression warrant investigation as predictive biomarkers for ICI response and as therapeutic targets in sarcomas.
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