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

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 <i>Kras</i> 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-β 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.

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Publication Details

Journal
Proceedings of the National Academy of Sciences
Published
2024-08-26
DOI
https://doi.org/10.1073/pnas.2402913121
Citations
13
Primary Topic
interferon and immune responses
Type
article
Field-Weighted Citation Impact
3.13

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article

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

Marina Salmón, Coral Fustero‐Torre, Chiara Ambrogio, Fátima Al‐Shahrour et al.
13 citations
Proceedings of the National Academy of Sciences
interferon and immune responses
3.13
article

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

Marina Salmón, Coral Fustero‐Torre, Chiara Ambrogio, Fátima Al‐Shahrour, Carmen Guerra, Ana Dopazo, Sergio Callejas, Rebeca Álvarez, Matthias Drosten, Alejandra López-García, Mariano Barbacid, Elena Piñeiro-Yáñez, David Santamarı́a, Carmen G. Lechuga, Mónica Musteanu, Fernando Fernández-García, Laura Esteban-Burgos, Haiyun Wang, Ana Fernández‐Rodríguez, Marta San Román
article en
13 citations

Abstract

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 <i>Kras</i> 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-β 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.

Proceedings of the National Academy of SciencesVol. 121(36)
Tongji University (CN), Universidad Complutense de Madrid (ES), Consejo Superior de Investigaciones Científicas (ES), Universidad de Salamanca (ES), Instituto de Salud Carlos III (ES), Spanish National Cancer Research Centre (ES), Centro de Investigación Biomédica en Red (ES), Centro de Investigación del Cáncer (ES), Centro de Investigación Biomédica en Red de Cáncer (ES), University of Turin (IT)
Ministerio de Ciencia, Innovación y Universidades, AXA Research Fund, European Regional Development Fund
Good health and well-being
Openalex Percentile: Top 8%
interferon and immune responses
3.13
DOIOpen Access PDFOpenAlex
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