| Title: |
High transposable element expression in sarcomas is associated with increased immune infiltrates and improved outcomes including after immunotherapy |
| Authors: |
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 G; Slotkin, Emily K; Rosenbaum, Evan; Avutu, Viswatej; Chan, Jason E; Banks, Lauren B; Adamson, Travis; Singer, Samuel; Antonescu, Cristina R; Tap, William D; Donoghue, Mark TA; D’Angelo, Sandra P |
| Contributors: |
Merck; Amgen; Damon Runyon Cancer Research Foundation; Henry R. Kravis Center for Molecular Oncology; Witherwax fund; Connective Tissue Oncology Society; Cycle for Survival; National Cancer Institute; NEKTAR; Bristol Myers Squibb; Incyte |
| Source: |
Journal for ImmunoTherapy of Cancer ; volume 13, issue 9, page e012357 ; ISSN 2051-1426 |
| Publisher Information: |
BMJ |
| Publication Year: |
2025 |
| Description: |
Background Response to immune checkpoint inhibition (ICI) in sarcomas is overall low and heterogeneous. Understanding determinants of ICI outcomes may improve efficacy and patient selection. Thus, we investigated whether the expression of transposable elements (TEs), which are epigenetically silenced and can stimulate antitumor immunity, influence ICI outcomes and immune infiltrates in common sarcoma subtypes. Methods We used transcriptomic data to assign immune enhanced versus immune depleted status to 67 pretreatment and on-treatment biopsies of sarcomas from patients treated on ICI trials, along with additional cohorts from The Cancer Genome Atlas (TCGA) and an independent ICI trial (SARC028). A machine learning technique (lasso-penalized logistic regression) controlled for sarcoma subtype was used to determine if TE and epigenetic regulatory gene expression predict immune infiltrates. Correlations between top features in these models and sarcoma immune infiltrates, immune pathway expression, and clinical outcomes were explored. Results Expression of TEs and epigenetic regulators significantly predicted immune enhanced status. TE subfamilies and Ikaros family zinc finger 1 ( IKZF1 ), a chromatin-modulating transcription factor, were significantly contributory. TE and IKZF1 expression positively correlated with tumor immune infiltrates, inflammatory pathways, and improved clinical outcomes, and increased in tumors that gained immune infiltrates during ICI treatment. TE and IKZF1 expression similarly correlated with overall survival and immune features in a TCGA cohort. In an additional cohort of patients with sarcoma treated with ICI, IKZF1 expression correlated with progression-free survival and inflammatory features. Conclusions TE and IKZF1 expression warrant further translational investigation as potential biomarkers of tumor immune infiltrates and outcomes following ICI treatment, and as therapeutic targets in sarcomas. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1136/jitc-2025-012357 |
| Availability: |
https://doi.org/10.1136/jitc-2025-012357; https://syndication.highwire.org/content/doi/10.1136/jitc-2025-012357 |
| Rights: |
http://creativecommons.org/licenses/by-nc/4.0/ |
| Accession Number: |
edsbas.3C63F448 |
| Database: |
BASE |