American Association for Cancer Research
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Supplementary Figure 2 from Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages

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posted on 2023-03-31, 18:20 authored by Don-Hong Wang, Hyun-Sung Lee, David Yoon, Gerald Berry, Thomas M. Wheeler, David J. Sugarbaker, Farrah Kheradmand, Edgar Engleman, Bryan M. Burt

Bitransgenic mice were fed dox for 7 weeks and treated with a depleting antibody against CSF-1R every other day. Expression of MHC-II and CD40 were evaluated by flow cytometry (A) and tumor burden was evaluated by H-E staining on lung tissue sections (B).


Thoracic Surgery Foundation



Purpose: Lung adenocarcinomas with mutations in the EGFR have unprecedented initial responses to targeted therapy against the EGFR. Over time, however, these tumors invariably develop resistance to these drugs. We set out to investigate alternative treatment approaches for these tumors.Experimental Design: To investigate the immunologic underpinnings of EGFR-mutant lung adenocarcinoma, we utilized a bitransgenic mouse model in which a mutant human EGFR gene is selectively expressed in the lungs.Results: EGFR oncogene–dependent progression and remission of lung adenocarcinoma was respectively dependent upon the expansion and contraction of alveolar macrophages, and the mechanism underlying macrophage expansion was local proliferation. In tumor-bearing mice, alveolar macrophages downregulated surface expression of MHC-II and costimulatory molecules; increased production of CXCL1, CXCL2, IL1 receptor antagonist; and increased phagocytosis. Depletion of alveolar macrophages in tumor-bearing mice resulted in reduction of tumor burden, indicating a critical role for these cells in the development of EGFR-mutant adenocarcinoma. Treatment of mice with EGFR-targeting clinical drugs (erlotinib and cetuximab) resulted in a significant decrease in alveolar macrophages in these mice. An activated alveolar macrophage mRNA signature was dominant in human EGFR-mutant lung adenocarcinomas, and the presence of this alveolar macrophage activation signature was associated with unfavorable survival among patients undergoing resection for EGFR-mutant lung adenocarcinoma.Conclusions: Because of the inevitability of failure of targeted therapy in EGFR-mutant non-small cell lung cancer (NSCLC), these data suggest that therapeutic strategies targeting alveolar macrophages in EGFR-mutant NSCLC have the potential to mitigate progression and survival in this disease. Clin Cancer Res; 23(3); 778–88. ©2016 AACR.

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