Author:
Nacev Benjamin A.,Bradic Martina,Woo Hyung Jun,Richards Allison L.,Kelly Ciara M.,Dickson Mark A.,Gounder Mrinal M.,Keohan Mary L.,Chi Ping,Movva Sujana,Maki Robert,Slotkin Emily K.,Rosenbaum Evan,Avutu Viswatej,Chan Jason E.,Banks Lauren,Adamson Travis,Singer Samuel,Antonescu Cristina R.,Tap William D.,Donoghue Mark T.A.,D’Angelo Sandra P.
Abstract
ABSTRACTResponse 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 andIKZF1, a chromatin-interacting transcription factor, were significantly contributory. TE andIKZF1expression 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 andIKZF1expression warrant investigation as predictive biomarkers for ICI response and as therapeutic targets in sarcomas.
Publisher
Cold Spring Harbor Laboratory