Exploring the Role of IL-1β/IL-1R in the Pathogenesis of K-ras Mutant Lung Cancer

Advisor: Seyed Javad Moghaddam, MD

As the leading cause of cancer-related deaths worldwide, the development of targeted therapeutics to treat lung cancer remains crucial. Non-small cell lung cancer (NSCLC), the most common histological subtype predominantly comprises lung adenocarcinoma with driver mutations in the K-ras oncogene (KM-LUAD). KM-LUAD progression partly occurs through activation of the NF-κB pathway initiating an inflammatory response and creating a pro-tumor microenvironment. Notably, the pro-inflammatory cytokine IL-1β a potent activator and product of the NF-κB pathway is elevated in the lungs and sera of KM-LUAD patients. We have shown that IL-1β blockade promotes an anti-tumor immune phenotype in a mouse model of KM-LUAD driven by lung epithelial cell-specific expression of KRAS^G12D (CCSP^Cre/LSL-KRAS^G12D, CC-LR mouse), suggesting that IL-1β mediates tumor-promoting inflammation. Yet, cell-specific mechanisms that underlie this effect are still poorly understood. Thus, we sought to elucidate the role of IL-1β signaling via its ability to bind to its receptor, IL-1R, by conditionally knocking out IL-1R in KRAS-mutant lung epithelial cells in CC-LR mice (LR/IL-1R^Δ/Δ). Tumor development as well as immune microenvironment in 14 and 18-week-old LR/IL-1R^Δ/Δ mice in comparison to age- and sex-matched control CC-LR littermates were studied. Notably a 30% reduction in tumor burden in LR/IL-1R^Δ/Δ mice was evident at both time points tested when compared to their CC-LR counterpart. Reduced tumorigenesis was shown to be driven by decreased in angiogenesis and an overall age dependent effect on tumor promoting inflammation was seen. Tumor reduction in 14-week-old LR/IL-1R^Δ/Δ mice was attributed to an abundance of myeloid cell subsets as well as shift in dendritic cell phenotype indicating an increase in T-cell priming. This differed in 18-week-old LR/IL-1R^Δ/Δ mice where a stronger response to epithelial IL-1R targeting with a significant depletion in T-cell associated markers as well as NF-κB activation were observed. Overall, these findings provide insight into cell-specific mechanisms underlying the tumor-promoting effects of IL-1β signaling and support the role of tumor cell-intrinsic factors in this process via shaping the tumor microenvironment.

Advisory Committee:
Seyed Javad Moghaddam, MD, Chair
Farrah Kheradmand, MD
Humam Kadara, PhD
Jyotika Sharma, PhD
Jianjun Zhang, MD, PhD

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