2020 Lung Cancer Research Foundation Annual Grant Program
Chengcheng Jin, PhD
University of Pennsylvania
Research Project:
Targeting the IL-1beta pathway for lung cancer treatment
Summary:
Chronic inflammation is closely associated with lung cancer and plays a critical role in tumor progression, and metastases. However, the source of such inflammation has not been clearly defined and the contribution of specific cellular and molecular component of the immune system is yet to be elucidated. Interleukin 1β (IL-1beta) has emerged as a key mediator of tumor-associated inflammation. Upregulation of IL-1beta in the tumor microenvironment (TME) has been shown to promote cancer cell proliferation, angiogenesis and tissue remodeling across different types of cancers. Of note, in a recent large, randomized, double-blind clinical trial, blockade of IL-1beta dramatically reduced lung cancer incidence and mortality in high-risk individual. However, the mechanisms underlying the generation of IL-1beta and its action in lung cancer remain poorly understood. As a mucosal organ harboring the largest surface area, the lung is colonized by a diverse bacterial community in both physiological and pathological conditions. Using a genetically engineered mouse model of lung adenocarcinoma, our previous work showed that tumor growth is associated with increased bacterial burden and altered bacterial composition in the lung. This dysregulated microbiota stimulate IL-1beta production from tumor-associated myeloid cells, triggering an inflammatory cascade. Our data pinpointed IL-1beta as a critical mediator of microbiota-immune interaction in lung cancer. Therefore, we hypothesize that selectively targeting the lung microbiota or the responding IL-1beta pathway can rewire the TME to reduce pro-tumorigenic inflammation while boost the anti-tumor immunity both at the baseline and in response to immunotherapies. The overarching goal of this study is to decipher the molecular mechanism by which active IL-1beta is generated in the lung TME, and to understand how IL-1beta shapes the tumor-associated immune response to affect lung cancer progression and response to immunotherapies.