Oncogenic RAS activity is linked to immune priming and adenosine-driven immune evasion in lung adenocarcinoma

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. Competing Interest Statement S.C.T. has acted as a consultant for Revolution Medicines. J.D. has acted as a consultant for AstraZeneca, Bayer, Novartis, TheRas, Vividion, Jubilant and has received research funding from AstraZeneca, Bristol Myers Squibb and Revolution Medicines. S.-H.L. reports serving in a consulting or advisory role for Abion, AstraZeneca, BeiGene, Bristol Myers Squibb, Daiichi Sankyo, Eli Lilly, IMBdx, ImmuneOncia, Janssen, Merck, MSD, Novartis, Pfizer, Roche, and Takeda; receiving honoraria from Amgen, AstraZeneca/MedImmune, Bristol Myers Squibb, MSD, Roche, and Yuhan; and receiving research funding from AstraZeneca, Daiichi Sankyo, Lunit, and MSD, outside of the current work. C.S. acknowledges grants from AstraZeneca, Boehringer-Ingelheim, Bristol Myers Squibb, Pfizer, Roche-Ventana, Invitae (previously Archer Dx Inc - collaboration in minimal residual disease sequencing technologies), Ono Pharmaceutical, and Personalis. He is Chief Investigator for the AZ MeRmaiD 1 and 2 clinical trials and is the Steering Committee Chair. He is also Co-Chief Investigator of the NHS Galleri trial funded by GRAIL and a paid member of GRAILs Scientific Advisory Board. He receives consultant fees from Achilles Therapeutics (also SAB member), Bicycle Therapeutics (also a SAB member), Genentech, Medicxi, China Innovation Centre of Roche (CICoR) formerly Roche Innovation Centre, Shanghai, Metabomed (until July 2022), and the Sarah Cannon Research Institute C.S. has received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, GlaxoSmithKline, Illumina, MSD, Novartis, Pfizer, and Roche-Ventana. C.S. has previously held stock options in Apogen Biotechnologies and GRAIL, and currently has stock options in Epic Bioscience, Bicycle Therapeutics, and has stock options and is co-founder of Achilles Therapeutics. Patents: C.S. declares a patent application (PCT/US2017/028013) for methods to lung cancer; targeting neoantigens (PCT/EP2016/059401); identifying patient response to immune checkpoint blockade (PCT/EP2016/071471), determining HLA LOH (PCT/GB2018/052004); predicting survival rates of patients with cancer (PCT/GB2020/050221), identifying patients who respond to cancer treatment (PCT/GB2018/051912); methods for lung cancer detection (US20190106751A1). C.S. is an inventor on a European patent application (PCT/GB2017/053289) relating to assay technology to detect tumour recurrence. This patent has been licensed to a commercial entity and under their terms of employment C.S. is due a revenue share of any revenue generated from such license(s).