Effect of depletion of KDM4D, NFIB, and MLL1 on gene expression during adipogenic differentiation of C3H10T1/2 mesenchymal stem cells
The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand alternative mechanisms governing local immunosuppression to fuel novel therapies. Elevated surfactant and GM-CSF secretion from the transformed epithelium induces tumor-associated alveolar macrophages (TA-AM) to proliferate and support tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF—PPAR? signaling and inhibition of airway GM-CSF or PPAR? in TA-AMs suppresses cholesterol efflux to tumor cells, which impairs EGFR phosphorylation and restrains LUAD progression. In the absence of TA-AM metabolic support, LUAD cells compensate by increasing cholesterol synthesis, and blocking PPAR? in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases T cell effector functions. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how such cancer cells can metabolically co-opt TA-AMs through GM-CSF—PPAR? signaling to provide nutrients that promote oncogenic signaling and growth. Overall design: Single-cell RNA sequencing of lungs from EGFR-mutant LUAD tumors with WT and PPAR?-/- macrophages or their littermate healthy controls.