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. 2024 Jan 25:OF1-OF22.
doi: 10.1158/2159-8290.CD-23-0434. Online ahead of print.

EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth

Alexandra Kuhlmann-Hogan  1   2 , Thekla Cordes  3   4   5 , Ziyan Xu  2   6 , Ramya S Kuna  3 , Kacie A Traina  2 , Camila Robles-Oteíza  1 , Deborah Ayeni  7 , Elizabeth M Kwong  8   9 , Stellar Levy  7 , Anna-Maria Globig  2 , Matthew M Nobari  10 , George Z Cheng  10 , Sandra L Leibel  8   9 , Robert J Homer  11 , Reuben J Shaw  3 , Christian M Metallo  3 , Katerina Politi  7   12 , Susan M Kaech  2
Affiliations

EGFR-Driven Lung Adenocarcinomas Co-opt Alveolar Macrophage Metabolism and Function to Support EGFR Signaling and Growth

Alexandra Kuhlmann-Hogan et al. Cancer Discov. .

Abstract

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.

Significance: Alternate strategies harnessing anticancer innate immunity are required for lung cancers with poor response rates to T cell-based immunotherapies. This study identifies a targetable, mutually supportive, metabolic relationship between macrophages and transformed epithelium, which is exploited by tumors to obtain metabolic and immunologic support to sustain proliferation and oncogenic signaling.

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