EGFR + lung adenocarcinomas coopt alveolar macrophage metabolism and function to support EGFR signaling and growth.

Abstract

The limited efficacy of currently approved immunotherapies in EGFR-mutant lung adenocarcinoma (LUAD) underscores the need to better understand mechanisms governing local immunosuppression. 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-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 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-PPARγ signaling to provide nutrients that promote oncogenic signaling and growth.

• Authors: Alexandra Kuhlmann-Hogan, Thekla Cordes, Ziyan Xu, Kacie A Traina, Camila Robles-Oteíza, Deborah Ayeni, Elizabeth M Kwong, Stellar R Levy, Mathew Nobari, George Z Cheng, Reuben Shaw, Sandra L Leibel, Christian M Metallo, Katerina Politi, Susan M Kaech
• Journal: bioRxiv : the preprint server for biology (bioRxiv) (Apr 17 2023) United States
• PMID: 37131637 (Publication Type: Preprint)