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
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA.
J Immunother Cancer. 2025 Sep 5;13(9):e012357. doi: 10.1136/jitc-2025-012357.
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.
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.
Expression of TEs and epigenetic regulators significantly predicted immune enhanced status. TE subfamilies and Ikaros family zinc finger 1 (), a chromatin-modulating transcription factor, were significantly contributory. TE and 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 expression similarly correlated with overall survival and immune features in a TCGA cohort. In an additional cohort of patients with sarcoma treated with ICI, expression correlated with progression-free survival and inflammatory features.
TE and expression warrant further translational investigation as potential biomarkers of tumor immune infiltrates and outcomes following ICI treatment, and as therapeutic targets in sarcomas.
肉瘤对免疫检查点抑制（ICI）的反应总体较低且存在异质性。了解ICI疗效的决定因素可能会提高疗效并优化患者选择。因此，我们研究了转座元件（TE）的表达是否会影响常见肉瘤亚型的ICI疗效和免疫浸润，TE在表观遗传上是沉默的，但可刺激抗肿瘤免疫。
我们使用转录组数据，对接受ICI试验治疗的患者的67份肉瘤治疗前和治疗中的活检样本，以及来自癌症基因组图谱（TCGA）的其他队列和一项独立的ICI试验（SARC028）进行免疫增强与免疫耗竭状态分类。使用一种控制肉瘤亚型的机器学习技术（套索惩罚逻辑回归）来确定TE和表观遗传调控基因的表达是否能预测免疫浸润。探讨了这些模型中顶级特征与肉瘤免疫浸润、免疫途径表达和临床结果之间的相关性。
TE和表观遗传调节因子的表达显著预测了免疫增强状态。TE亚家族和染色质调节转录因子IKZF1有显著贡献。TE和IKZF1的表达与肿瘤免疫浸润、炎症途径呈正相关，并改善临床结果，且在ICI治疗期间获得免疫浸润的肿瘤中增加。在TCGA队列中，TE和IKZF1的表达与总生存期和免疫特征也有类似的相关性。在另一组接受ICI治疗的肉瘤患者中，IKZF1的表达与无进展生存期和炎症特征相关。
TE和IKZF1的表达作为肿瘤免疫浸润和ICI治疗后结果潜在生物标志物，以及肉瘤的治疗靶点，值得进一步开展转化研究。
