Englander Ryan P, Brugiolo Mattia, Wu Te-Chia, Kostich Mitch, Leclair Nathan K, Park SungHee, Banchereau Jacques, Yu Peter, Salner Andrew, Banchereau Romain, Palucka Karolina, Anczuków Olga
The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Graduate Program in Immunology, UConn Health, Farmington, CT, USA.
bioRxiv. 2025 Aug 19:2025.08.19.671121. doi: 10.1101/2025.08.19.671121.
Immunotherapy benefits only a subset of lung cancer patients, and the molecular determinants of variable outcomes remain unclear. Using long-read RNA-sequencing we mapped the landscape of alternative RNA splicing in human primary lung adenocarcinomas. We identified over 180,000 full-length mRNA isoforms, more than half of which were novel and many of which occurred in immune-related genes, particularly within the type I interferon response pathway. We discovered retained introns in the gene that produce altered protein isoforms that regulate immune signaling and interferon responses. Furthermore, intron retention levels predicted patient responses to checkpoint inhibitors. These findings position alternative splicing as a key regulator of tumor immune responses and reveal mRNA splicing alterations as potential biomarkers to identify patients who might respond to cancer immunotherapy.
免疫疗法仅使一部分肺癌患者受益，而疗效各异的分子决定因素仍不清楚。我们使用长读长RNA测序技术描绘了人类原发性肺腺癌中可变RNA剪接的全貌。我们鉴定出超过180,000种全长mRNA异构体，其中一半以上是新发现的，且许多出现在免疫相关基因中，尤其是在I型干扰素反应途径内。我们在产生调节免疫信号和干扰素反应的改变蛋白异构体的基因中发现了保留内含子。此外，内含子保留水平可预测患者对检查点抑制剂的反应。这些发现将可变剪接定位为肿瘤免疫反应的关键调节因子，并揭示mRNA剪接改变作为识别可能对癌症免疫疗法有反应的患者的潜在生物标志物。
