The Role of Tumour Intrinsic Inflammasome Mutations in Lung Adenocarcinoma.

Abstract

Introduction: Lung adenocarcinoma (LUAD) is the most common form of lung cancer and the leading cause of cancer related death. In 2017, immune checkpoint inhibitors (ICI)s were approved as part of the frontline LUAD treatment regime. However, only about 20% of non-stratified LUAD patients respond to ICI monotherapy, and predicting the response of individual patients remains challenging. The innate immune system is critical and necessary for maturation and activity of the adaptive immune system and offers opportunities to enhance the response to ICIs. Indeed, the importance of the innate immune cytokine, IL-1b in the development of LUAD was revealed by the phase III CANTOS trial which recorded a staggering 67% and 77% reduction in lung cancer incidence and mortality respectively. However, IL-1b neutralization in patients with existing LUAD failed to meet primary efficacy endpoints. Together this highlights the potential of harnessing the innate immune system in the treatment of LUAD but to do so requires a deep understanding of the inflammatory environment throughout the development of LUAD. Method(s): We combine patient data with autochthonous mouse models of LUAD and spatial transcriptomics to interrogate the importance of the inflammasome in Kras driven LUAD development. Result(s): Our data show activating mutations in the inflammasome are prevalent in LUAD, which are accompanied by transcriptomic changes in tumor microenvironment. Tumor intrinsic deletion of the inflammasome significantly delays disease onset. Conclusion(s): The inflammasome plays a key role in the development of lung adenocarcinoma and offers a novel therapeutic opportunity.