Multimodal profiling of proinflammatory protease activity identifies caspase-1 as a target for lung cancer interception

Abstract The systemic inhibition of IL-1b, a key mediator of pulmonary inflammation, has been shown to reduce the incidence of lung cancer in patients in years following treatment, but knowledge gaps surrounding its activation and role in the tumor microenvironment are hindering approaches for cancer interception. We developed a suite of activity-based technologies to probe inflammation in early lung cancer and identified a translational target candidate. We designed probes sensitive to various IL-1b-activating proteases and applied them to a murine model of inflammatory lung cancer, Kras/Trp53-mutant with SIINFEKL expression (KPS). Our nanosensors revealed reduced cleavage of a caspase-1 reporter in the lungs of KPS mice treated with IL-1b antibody, as well as elevated caspase-1 expression and activity in naïve tumor tissue sections, highlighting the importance of caspase-1 processing of IL-1b during cancer development. We conducted a pre-clinical trial of a novel combination intervention by administering both IL-1b blockade and caspase-1 inhibition shortly after tumor induction. Following treatment, we observed significant reduction in lung cancer formation, including complete ablation of tumor incidence in nearly 20% of KPS mice. Our approach to understand the interplay of protease activity and cytokine activation supports development of new strategies to mitigate inflammation and intercept lung cancer progression. Competing Interest Statement A provisional patent has been filed on this work: Profiling inflammation-associated protease activity in early lung cancer (CSW, SNB). SNB reports consulting roles, board membership, and/or equity in Global Oncology, Sunbird Bio, Satellite Bio, Matrisome Bio, Xilio Therapeutics, Danaher, Catalio Capital, Pictet, Ochre Bio, Amplifyer Bio, Earli Inc., Impilo Therapeutics, Port Therapeutics, Vertex Pharmaceuticals, Ropirio Therapeutics, and Moderna and receives sponsored research funding from Open Philanthropy and Owlstone Medical, which were not involved in this study. TEJ reports consulting roles, board membership, and/or equity in Amgen, Thermo Fisher Scientific, Dragonfly Therapeutics, T2 Biosystems, SQZ Biotech, Skyhawk Therapeutics, and Break Through Cancer and receives sponsored research funding from the Lustgarten Foundation, which were not involved in this study. The remaining authors report no competing interests.