Intron retention regulates STAT2 function and associates with immunotherapy response in lung cancer

IF 47.3 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2026-10-22 DOI:10.1126/science.aea7156

Ryan P. Englander, Mattia Brugiolo, Maëva Devoucoux, Te-Chia Wu, Mitch Kostich, Nathan K. Leclair, Isha Walawalkar, Hyeon Gu Kang, SungHee Park, Florentina Marches, Mark E. Peeples, Phylip Chen, Jacques Banchereau, Peter Yu, Andrew Salner, Romain Banchereau, Karolina Palucka, Olga Anczuków

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Abstract

Immunotherapy with checkpoint inhibitors has revolutionized cancer therapy and enabled considerable therapeutic advances for treating various diseases, including lung cancer. However, the molecular determinants of variable patient outcomes remain unclear. Using long-read RNA sequencing, we mapped the landscape of alternative RNA splicing in human primary lung adenocarcinomas. We identified more than 149,000 full-length messenger RNA (mRNA) isoforms, more than half of which were unannotated and many that occurred in immune-related genes, particularly within the type I interferon response pathway. We functionally characterized retained introns in the STAT2 gene that produced altered protein isoforms that regulated immune signaling and interferon responses and correlated with patient survival after anti–programmed death-ligand 1 (PD-L1) immunotherapy. These findings position alternative splicing as a regulator of tumor immune responses and reveal intron retention in STAT2 as an interferon regulatory axis that correlates with PD-L1 checkpoint inhibitor response.

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内含子保留调节STAT2功能并与肺癌免疫治疗应答相关

使用检查点抑制剂的免疫疗法已经彻底改变了癌症治疗，并使包括肺癌在内的各种疾病的治疗取得了相当大的进展。然而，患者预后变化的分子决定因素仍不清楚。使用长读RNA测序，我们绘制了人类原发性肺腺癌中选择性RNA剪接的景观。我们鉴定了超过149,000个全长信使RNA （mRNA）异构体，其中一半以上是未注释的，许多发生在免疫相关基因中，特别是在I型干扰素反应途径中。我们在功能上表征了STAT2基因中保留的内含子，这些内含子产生改变的蛋白亚型，调节免疫信号和干扰素反应，并与抗程序性死亡配体1 （anti -程序性死亡配体1，PD-L1）免疫治疗后的患者生存率相关。这些发现将选择性剪接定位为肿瘤免疫应答的调节因子，并揭示STAT2中的内含子保留是与PD-L1检查点抑制剂应答相关的干扰素调节轴。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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