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Updated: Sep 16, 2025
Visualization of Inflammatory Caspases Induced Proximity in Human Monocyte-Derived Macrophages
Published on: April 6, 2022
Multimodal profiling of proinflammatory protease activity identifies caspase-1 as a target for lung cancer
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.
Insights
Targeting interleukin-1 beta (IL-1b) and caspase-1 with novel probes and combination therapy significantly reduced lung cancer formation in preclinical models. This approach offers new strategies for intercepting pulmonary inflammation and cancer progression.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Interleukin-1 beta (IL-1b) is a key mediator of pulmonary inflammation, and its systemic inhibition can reduce lung cancer incidence.
- Knowledge gaps regarding IL-1b activation and its role in the tumor microenvironment hinder effective cancer interception strategies.
Purpose of the Study:
- To develop activity-based technologies to probe inflammation in early lung cancer.
- To identify and validate a translational target for cancer interception.
- To investigate the efficacy of combined IL-1b blockade and caspase-1 inhibition in a preclinical lung cancer model.
Main Methods:
- Development of probes sensitive to IL-1b-activating proteases.
- Application of nanosensors to a Kras/Trp53-mutant murine lung cancer model (KPS).
- Pre-clinical trial combining IL-1b blockade and caspase-1 inhibition post-tumor induction.
Main Results:
- Nanosensors revealed reduced caspase-1 reporter cleavage in IL-1b antibody-treated KPS mice.
- Elevated caspase-1 expression and activity were observed in naïve tumor tissue.
- Combination therapy significantly reduced lung cancer formation, with complete ablation in nearly 20% of mice.
Conclusions:
- Caspase-1 processing of IL-1b is crucial during lung cancer development.
- Combined IL-1b blockade and caspase-1 inhibition represent a promising strategy for lung cancer interception.
- This approach aids in developing new methods to mitigate inflammation and intercept cancer progression.
