title: Epithelial-Mesenchymal Transition Is Associated with a Distinct Tumor Microenvironment Including Elevation of Inflammatory Signals and Multiple Immune Checkpoints in Lung Adenocarcinoma.
abstract: Promising results in the treatment of non-small cell lung cancer (NSCLC) have been seen with agents targeting immune checkpoints, such as programmed cell death 1 (PD-1) or programmed death ligand-1 (PD-L1). However, only a select group of patients respond to these interventions. The identification of biomarkers that predict clinical benefit to immune checkpoint blockade is critical to successful clinical translation of these agents.
  
  
  
  We conducted an integrated analysis of three independent large datasets, including The Cancer Genome Atlas of lung adenocarcinoma and two datasets from MD Anderson Cancer Center (Houston, TX), Profiling of Resistance Patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax (named PROSPECT) and Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (named BATTLE-1). Comprehensive analysis of mRNA gene expression, reverse-phase protein array, IHC, and correlation with clinical data were performed.
  
  
  
  Epithelial-mesenchymal transition (EMT) is highly associated with an inflammatory tumor microenvironment in lung adenocarcinoma, independent of tumor mutational burden. We found immune activation coexistent with elevation of multiple targetable immune checkpoint molecules, including PD-L1, PD-L2, PD-1, TIM-3, B7-H3, BTLA, and CTLA-4, along with increases in tumor infiltration by CD4(+)Foxp3(+) regulatory T cells in lung adenocarcinomas that displayed an EMT phenotype. Furthermore, we identify B7-H3 as a prognostic marker for NSCLC.
  
  
  
  The strong association between EMT status and an inflammatory tumor microenvironment with elevation of multiple targetable immune checkpoint molecules warrants further investigation of using EMT as a predictive biomarker for immune checkpoint blockade agents and other immunotherapies in NSCLC and possibly a broad range of other cancers. Clin Cancer Res; 22(14); 3630-42. ©2016 AACRSee related commentary by Datar and Schalper, p. 3422.
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Yanyan
authors: Y
authors: Lou
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lixia
authors: L
authors: Diao
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Edwin Roger Parra
authors: ER
authors: Cuentas
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Warren L
authors: WL
authors: Denning
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Limo
authors: L
authors: Chen
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: You Hong
authors: YH
authors: Fan
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Lauren A
authors: LA
authors: Byers
authors: Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jing
authors: J
authors: Wang
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Vassiliki A
authors: VA
authors: Papadimitrakopoulou
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Carmen
authors: C
authors: Behrens
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Jaime Canales
authors: JC
authors: Rodriguez
authors: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Patrick
authors: P
authors: Hwu
authors: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors: Ignacio I
authors: II
authors: Wistuba
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. dlgibbon@mdanderson.org jheymach@mdanderson.org.
authors: John V
authors: JV
authors: Heymach
authors: Department of Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston. dlgibbon@mdanderson.org jheymach@mdanderson.org.
authors: Don L
authors: DL
authors: Gibbons
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents / Q000627:therapeutic use; D060887:B7 Antigens / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation / Q000378:metabolism / Q000473:pathology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D060887:B7 Antigens; D014408:Biomarkers, Tumor