Abstract LB359: Lung epithelial specific IL-1R promotes K-ras mutant lung cancer by inducing angiogenesis that might be medicated via myeloid tumor microenvironment

Abstract As the leading cause of cancer-related deaths worldwide, the development of targeted therapeutics and immunotherapies as a means for treating lung cancer remains crucial. Non-small cell lung cancer (NSCLC), the most common histological subtype accounting for 85%, predominantly arises from lung adenocarcinoma with driver mutations in the K-ras oncogene (KM-LUAD). Studies have shown that 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. Our preliminary studies have shown that IL-1β blockade reprograms the lung immune microenvironment to that of an anti-tumor immune phenotype in a mouse model of KM-LUAD driven by lung epithelial cell-specific expression of KRASG12D (CCSPCre/LSL-KRASG12D, CC-LR mouse), suggesting that indeed this cytokine mediates tumor-promoting inflammation in KM-LUAD pathogenesis. Yet, cell-specific mechanisms that underlie tumor-promoting roles of IL-1β signaling 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, in the context of KM-LUAD by conditionally knocking out the IL-1R in KRAS-mutant lung epithelial cells in CC-LR mice. Tumor development as well as immune microenvironment in 14 and 18-week-old CC-LR mice with epithelial specific conditional knockout of IL-1R (LR/IL-1RΔ/Δ) in comparison to age- and sex-matched control CC-LR littermates were studied. Notably reduced tumor burden in LR/IL-1RΔ/Δ mice with an interesting shift toward atypical adenomatous hyperplasia (AHH) lesion formation was evident when compared to their CC-LR counterpart. Having previously shown that targeting IL-1R leads to a reduction in the myeloid cell compartment also known for the regulation and production of angiogenic markers, an immunohistochemical evaluation of the angiogenic marker ERG was performed, showing a significantly diminished expression in tissue collected from LR/IL-1RΔ/Δ mice. Further studies assessing the role of angiogenic modulation by IL-1R in the context of KM-LUAD progression and its regulation by myeloid cells are currently under investigation. 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 tumor progression via shaping the tumor microenvironment. Citation Format: Avantika Krishna, Michael J. Clowers, Bo Yuan, Vivian Ha, Katherine Larsen, Nastaran Karimi, Arnav Gaitonde, Jocelynn Colunga, Maria T. Grimaldo, Maria Jose Arredondo Sancristobal, Valentina Villalba-Sabat, Angelica Baca De Anda, Yasmina Rezai, Jyotika Sharma, Humam Kadara, Seyed Javad Moghaddam. Lung epithelial specific IL-1R promotes K-ras mutant lung cancer by inducing angiogenesis that might be medicated via myeloid tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB359.