title: Progression of EGFR-Mutant Lung Adenocarcinoma is Driven By Alveolar Macrophages.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Stanford University School of Medicine, Stanford, California.
authors: Don-Hong
authors: DH
authors: Wang
authors: Baylor College of Medicine, Houston, Texas.
authors: Hyun-Sung
authors: HS
authors: Lee
authors: Baylor College of Medicine, Houston, Texas.
authors: David
authors: D
authors: Yoon
authors: Stanford University School of Medicine, Stanford, California.
authors: Gerald
authors: G
authors: Berry
authors: Baylor College of Medicine, Houston, Texas.
authors: Thomas M
authors: TM
authors: Wheeler
authors: Baylor College of Medicine, Houston, Texas.
authors: David J
authors: DJ
authors: Sugarbaker
authors: Baylor College of Medicine, Houston, Texas.
authors: Farrah
authors: F
authors: Kheradmand
authors: Stanford University School of Medicine, Stanford, California.
authors: Edgar
authors: E
authors: Engleman
authors: Baylor College of Medicine, Houston, Texas. bryan.burt@bcm.edu.
authors: Bryan M
authors: BM
authors: Burt
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use; D000068818:Cetuximab / Q000627:therapeutic use; D004002:Clodronic Acid / Q000627:therapeutic use; D016207:Cytokines / Q000096:biosynthesis; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000069347:Erlotinib Hydrochloride / Q000627:therapeutic use; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005813:Genes, Synthetic; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008262:Macrophage Activation; D016676:Macrophages, Alveolar / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D020411:Oligonucleotide Array Sequence Analysis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012907:Smoking / Q000235:genetics; D014598:Uteroglobin / Q000235:genetics
chemical_list: D000074322:Antineoplastic Agents, Immunological; D016207:Cytokines; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011993:Recombinant Fusion Proteins; C556390:Scgb1a1 protein, mouse; D004002:Clodronic Acid; D014598:Uteroglobin; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab