Abstract 1355: Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development

Abstract Previously we reported that bone marrow-derived macrophages are required for lung squamous cell carcinoma development in kinase-dead Ikkα knockin (KA/KA) mice. The KA/KA lungs display strikingly enlarged sizes, sustained inflammation with increased expression of multiple cytokines and chemokines and marked infiltrating macrophages and T cells, and tissue damage, which look like a “burning hill”. To determine a critical event for the pathogenesis of the lung disease and SCC development, in this study, we found that these F4/80+CD11b+CSF1R+ monocyte-derived macrophages isolated from KA/KA lungs showed enlarged sizes carrying many lipid droplets and highly expressed the genes that encode proteins involved in lipid metabolism compared to WT. To determine whether the lung lipid concentrations regulate foamy macrophage development, we incubated Raw macrophages with WT or KA/KA lung extract, respectively, and found that KA/KA lung extracts induced lipid droplets and elevated lipid levels and pathways for lipid metabolism compared to WT lung extracts. Furthermore, we found that cytokines including IL-4, IL-6, IL-33, and IFNb, promoted lipid metabolism in Raw macrophages incubated with WT lung extracts, and also stimulated lipid metabolism in human lung SCC SW900 cells. These results suggest that these cytokines, which were highly expressed in KA/KA lungs, contribute to aberrant lipid metabolism. Because IL-4, which is produced by Th2 T cells, promoted lipid metabolism in macrophages and lung SCC cells, we further showed that KA/KA lung CD4 T cells stimulated lipid gene expression in Raw macrophages compared to WT lung CD4 T cells. Depleting CD4 T cells indeed significantly decreased foamy macrophage formation in the lungs of KA/KA mice. Importantly, treatment with a lipid inhibitor reduced IL-4-mediated lipid metabolism in Raw macrophages and human lung SCC SW900 cells, as well as this treatment attenuated lung foamy macrophage numbers and dampened lung SCC development in irradiated KA/KA mice with KA/KA bone marrow transplants. These findings highlight that the interplay between CD4 T cells, macrophages, cytokines, and epithelial cells contribute to a series of biological events in a landscape scale, which promote lung disease and lung SCC development through aberrant lipid metabolism. Citation Format: Gongping Shi, Sayantan Banerjee, Xin Li, Gajendra Jogdand, Yongmei Zhao, Kunio Nagashima, Thorkell Andresson, Jyoti Shetty, Bao Tran, Yinling Hu. Lipid-rich foamy macrophages along with CD4 T cell-derived signaling drive aberrant lipid metabolism and are a cause of lung cancer development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1355.