Author ORCID Identifier
0000-0002-1705-4115
Date of Graduation
5-2024
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Seyed Javad Moghaddam, M.D.
Committee Member
Jyotika Sharma, M.Phil., Ph.D.
Committee Member
Humam Kadara, Ph.D.
Committee Member
Farrah Kheradmand, M.D.
Committee Member
Jianjun Zhang, M.D., Ph.D.
Abstract
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 K-rasG12D (CCSPCre/LSL-K-rasG12D, 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 K-ras-mutant lung epithelial cells in CC-LR mice (LR/IL-1RΔ/Δ). Tumor development as well as immune microenvironment in 14 and 18-week-old LR/IL-1RΔ/Δ mice in comparison to control CC-LR littermates were studied. Notably a 30% reduction in tumor burden in LR/IL-1RΔ/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 angiogenesis and an overall age-dependent effect on tumor-promoting inflammation was seen. Tumor reduction in 14-week-old LR/IL-1RΔ/Δ mice was associated with an abundance of myeloid cell subsets as well as a shift in dendritic cell phenotype suggesting an increase in T-cell priming. This differed in 18-week-old LR/IL-1RΔ/Δ mice where a stronger response to epithelial IL-1R targeting with a significant reduction in T-cell associated markers as well as NF-κB activation was 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.
Keywords
NF-κB Pathway, Non-Small Cell Lung Cancer, IL-1β, IL-1R, Conditional Receptor Targeting, KRAS, Tumor Microenvironment, Angiogenesis, Stemness, Early and Late-Stage Tumorigenesis