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.
","abstract_html":"<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<sup>G12D</sup> (CCSP<sup>Cre</sup>/LSL-K-ras<sup>G12D</sup>, 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<sup>Δ/Δ</sup>). Tumor development as well as immune microenvironment in 14 and 18-week-old LR/IL-1R<sup>Δ/Δ</sup> mice in comparison to control CC-LR littermates were studied. Notably a 30% reduction in tumor burden in LR/IL-1R<sup>Δ/Δ</sup> 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<sup>Δ/Δ</sup> 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<sup>Δ/Δ</sup> 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>","abstract_has_math":false,"creators":["Krishna, Avantika","0000-0002-1705-4115
"],"institution":null,"degree_name":"Masters of Science (MS)","degree_level":"Thesis (MS)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Seyed Javad Moghaddam, M.D.","Jyotika Sharma, M.Phil., Ph.D.","Humam Kadara, Ph.D."],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2024,"date_issued":"2024-05-01T07:00:00Z","date_published":"2024-05-01T07:00:00Z","updated_at":"2026-07-24T05:49:08Z","subjects":["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"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1360","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Seyed Javad Moghaddam, M.D.","Jyotika Sharma, M.Phil., Ph.D.","Humam Kadara, Ph.D."]},{"key":"dc:creator","label":"Author","values":["Krishna, Avantika","0000-0002-1705-4115
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"]},{"key":"dc:title","label":"Title","values":["Exploring the Role of IL-1β/IL-1R in the Pathogenesis of K-ras Mutant Lung Cancer"]}]}],"canonical_facts":{"dc:contributor":["Seyed Javad Moghaddam, M.D.","Jyotika Sharma, M.Phil., Ph.D.","Humam Kadara, Ph.D."],"dc:creator":["Krishna, Avantika","0000-0002-1705-4115
"],"dc:date.available":["2024-04-26T07:00:00Z"],"dc:description.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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1360"],"dc:subject":["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"],"dc:title":["Exploring the Role of IL-1β/IL-1R in the Pathogenesis of K-ras Mutant Lung Cancer"],"thesis:degree_level":["Thesis (MS)"],"thesis:degree_name":["Masters of Science (MS)"]},"updated_at":"2026-07-24T05:49:08Z"}