Type I interferon signaling pathway enhances immune- checkpoint inhibition in KRAS mutant lung tumors

• 成果类型: Article
• 署名作者: Fernandez-Garcia, Fernando; Fernandez-Rodriguez, Ana; Fustero-Torre, Coral; Pineiro-Yanez, Elena; Wang, Haiyun; Lechuga, Carmen G.; Callejas, Sergio; Alvarez, Rebeca; Lopez-Garcia, Alejandra; Esteban-Burgos, Laura; Salmon, Marina; San Roman, Marta; Guerra, Carmen; Ambrogio, Chiara; Drosten, Matthias; Santamaria, David; Al Shahrour, Fatima; Dopazo, Ana; Barbacid, Mariano; Musteanu, Monica
• 署名单位: Tongji University; Centro Nacional de Investigaciones Cardiovasculares (CNIC); Instituto de Salud Carlos III; CIBER - Centro de Investigacion Biomedica en Red; CIBERONC; University of Turin; Consejo Superior de Investigaciones Cientificas (CSIC); University of Salamanca; Instituto de Salud Carlos III; CIBER - Centro de Investigacion Biomedica en Red; CIBERCV; Complutense University of Madrid; Helmholtz Association; Max Delbruck Center for Molecular Medicine
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11835
• DOI: 10.1073/pnas.2402913121
• 发表日期: 2024-09-03
• 关键词: cancer; cell; driven; activation; induction; origin; genes; stage

摘要

Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co- occurring mutations. Single- cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-beta or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically cold to immunologically hot tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co- occurring mutations in p53 or LKB1.