EGFR-driven lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth
Menée à l'aide de lignées cellulaires, de modèles murins d'adénocarcinome du poumon induit par le récepteur EGFR et d'échantillons de lavages broncho-alvéolaires d'origine humaine, cette étude met en évidence un mécanisme par lequel les cellules cancéreuses, en exploitant les relations métaboliques entre les macrophages alvéolaires associés à la tumeur et le tissu épithélial transformé, favorisent la signalisation oncogène et la croissance tumorale
The limited efficacy of currently approved immunotherapies in EGFR-driven 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 macrophage (TA-AM) proliferation which supports tumor growth by rewiring inflammatory functions and lipid metabolism. TA-AM properties are driven by increased GM-CSF—PPARγ signaling and inhibition of airway GM-CSF or PPARγ 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 PPARγ in TA-AMs simultaneous with statin therapy further suppresses tumor progression and increases proinflammatory immune responses. These results reveal new therapeutic combinations for immunotherapy resistant EGFR-mutant LUADs and demonstrate how cancer cells can metabolically co-opt TA-AMs through GM-CSF—PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.
Cancer Discovery 2024