Oncogenic RAS activity is linked to immune priming and adenosine-driven immune evasion in lung adenocarcinoma
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Sophie de Carne Phil East Claire E Pillsbury Mariana Silva Dos Santos Hongui Cha Emma Colliver Tegan Gilmore Sareena Rana Christopher Moore Scott Lighterness Deborah Caswell Jesse Boumelha Mona Tomaschko Romain Baer Jim Eyles Beatriz Teixeira Muhammad Saeed Kevin Litchfield Miriam Molina Arcas Se-Hoon Lee James MacRae Philip Hobson Charles Swanton Julian DownwardThis article is a preprint. Preprints have not been peer-reviewed.
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Abstract
Lung adenocarcinoma (LUAD) is a leading cause of cancer death worldwide, with RAS signalling as a key oncogenic driver. Although KRAS mutations have been linked to immune evasion in preclinical models, the relationship between RAS activity and tumour immunity or response to immunotherapy in patients remains unclear. Here, we applied our previously validated RAS84 transcriptional signature to stratify LUAD patient cohorts and dissect the immune landscape associated with RAS signalling. We report that tumours with elevated RAS activity exhibited features of immune priming, including increased immune infiltration, interferon response, and immune checkpoint gene expression, and showed improved progression-free survival in an independent cohort of patients treated with anti-PD-1. Yet, in both LUAD tumours and cell lines, RAS activity also correlated with elevated immunosuppressive interstitial adenosine mediated by transcriptional regulation of several components of the adenosinergic pathway. In orthotopic pre-clinical models of high-RAS activity lung tumours, blocking adenosine signalling delayed tumour growth and improved response to anti-PD-1 and KRAS inhibition, with a significant effect on innate immunity. This study reveals a dual role for RAS signalling in tumour progression, fostering a pro-immunogenic environment whilst simultaneously dampening anti-tumoural immunity via mechanisms including extracellular adenosine accumulation. Stratifying patients based on RAS transcriptional activity, rather than genetic alterations alone, could inform immunotherapy strategies and improve clinical outcomes.
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