Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma

Yanyan Lou, Lixia Diao, Edwin Roger Parra Cuentas, Warren L. Denning, Limo Chen, You Hong Fan, Lauren A. Byers, Jing Wang, Vassiliki A. Papadimitrakopoulou, Carmen Behrens, Jaime Canales Rodriguez, Patrick Hwu, Ignacio I. Wistuba, John V. Heymach, Don L. Gibbons

Research output: Contribution to journalArticle

133 Citations (Scopus)

Abstract

Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)3630-3642
Number of pages13
JournalClinical Cancer Research
Volume22
Issue number14
DOIs
StatePublished - Jul 15 2016
Externally publishedYes

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Epithelial-Mesenchymal Transition
Tumor Microenvironment
Non-Small Cell Lung Carcinoma
Biomarkers
Neoplasms
Programmed Cell Death 1 Ligand 2 Protein
Cell Death
Protein Array Analysis
Atlases
Regulatory T-Lymphocytes
Tumor Burden
Immunotherapy
Lung Neoplasms
Thorax
Adenocarcinoma of lung
Genome
Ligands
Phenotype
Gene Expression
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. / Lou, Yanyan; Diao, Lixia; Cuentas, Edwin Roger Parra; Denning, Warren L.; Chen, Limo; Fan, You Hong; Byers, Lauren A.; Wang, Jing; Papadimitrakopoulou, Vassiliki A.; Behrens, Carmen; Rodriguez, Jaime Canales; Hwu, Patrick; Wistuba, Ignacio I.; Heymach, John V.; Gibbons, Don L.

In: Clinical Cancer Research, Vol. 22, No. 14, 15.07.2016, p. 3630-3642.

Research output: Contribution to journalArticle

Lou, Y, Diao, L, Cuentas, ERP, Denning, WL, Chen, L, Fan, YH, Byers, LA, Wang, J, Papadimitrakopoulou, VA, Behrens, C, Rodriguez, JC, Hwu, P, Wistuba, II, Heymach, JV & Gibbons, DL 2016, 'Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma', Clinical Cancer Research, vol. 22, no. 14, pp. 3630-3642. https://doi.org/10.1158/1078-0432.CCR-15-1434
Lou, Yanyan ; Diao, Lixia ; Cuentas, Edwin Roger Parra ; Denning, Warren L. ; Chen, Limo ; Fan, You Hong ; Byers, Lauren A. ; Wang, Jing ; Papadimitrakopoulou, Vassiliki A. ; Behrens, Carmen ; Rodriguez, Jaime Canales ; Hwu, Patrick ; Wistuba, Ignacio I. ; Heymach, John V. ; Gibbons, Don L. / Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 14. pp. 3630-3642.
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abstract = "Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.",
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T1 - Epithelial-mesenchymal transition is associated with a distinct tumor microenvironment including elevation of inflammatory signals and multiple immune checkpoints in lung adenocarcinoma

AU - Lou, Yanyan

AU - Diao, Lixia

AU - Cuentas, Edwin Roger Parra

AU - Denning, Warren L.

AU - Chen, Limo

AU - Fan, You Hong

AU - Byers, Lauren A.

AU - Wang, Jing

AU - Papadimitrakopoulou, Vassiliki A.

AU - Behrens, Carmen

AU - Rodriguez, Jaime Canales

AU - Hwu, Patrick

AU - Wistuba, Ignacio I.

AU - Heymach, John V.

AU - Gibbons, Don L.

PY - 2016/7/15

Y1 - 2016/7/15

N2 - Purpose: 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. Methods: 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. Results: 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. Conclusions: 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.

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