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

<p>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-ras^G12D (CCSP^Cre/LSL-K-ras^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 K-ras-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 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 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 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-1R^Δ/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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2024

Authors dc:creator

• Krishna, Avantika
• <p>0000-0002-1705-4115</p>

Contributors dc:contributor

• Seyed Javad Moghaddam, M.D.
• Jyotika Sharma, M.Phil., Ph.D.
• Humam Kadara, Ph.D.

• 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
• Cancer Biology
• Immunology and Infectious Disease
• Immunotherapy
• Life Sciences

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1360

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2417