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Alterations of immune response of non-small lung cancer with azacytidine

John Wrangle, Wei Wang, Alexander Koch (UGent) , Hariharan Easwaran, Helai P Mohammad, Frank Vendetti, Wim Van Criekinge (UGent) , Tim De Meyer (UGent) , Zhengzong Du, Princy Parsana, et al.
(2013) ONCOTARGET. 4(11). p.2067-2079
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Abstract
Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.
Keywords
azacytidine, HDAC inhibitor, non-small cell lung cancer (nsclc), SET ENRICHMENT ANALYSIS, DEMETHYLATING AGENTS, INNATE IMMUNITY, TUMOR ESCAPE, DNA, EXPRESSION, GENES, INTERFERON, METHYLTRANSFERASE, IMMUNOTHERAPY

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Citation

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MLA
Wrangle, John, et al. “Alterations of Immune Response of Non-Small Lung Cancer with Azacytidine.” ONCOTARGET, vol. 4, no. 11, 2013, pp. 2067–79.
APA
Wrangle, J., Wang, W., Koch, A., Easwaran, H., Mohammad, H. P., Vendetti, F., … Baylin, S. B. (2013). Alterations of immune response of non-small lung cancer with azacytidine. ONCOTARGET, 4(11), 2067–2079.
Chicago author-date
Wrangle, John, Wei Wang, Alexander Koch, Hariharan Easwaran, Helai P Mohammad, Frank Vendetti, Wim Van Criekinge, et al. 2013. “Alterations of Immune Response of Non-Small Lung Cancer with Azacytidine.” ONCOTARGET 4 (11): 2067–79.
Chicago author-date (all authors)
Wrangle, John, Wei Wang, Alexander Koch, Hariharan Easwaran, Helai P Mohammad, Frank Vendetti, Wim Van Criekinge, Tim De Meyer, Zhengzong Du, Princy Parsana, Kristen Rodgers, Ray-Whay Yen, Cynthia A Zahnow, Janis M Taube, Julie R Brahmer, Scott S Tykodi, Keith Easton, Richard D Carvajal, Peter A Jones, Peter W Laird, Daniel J Weisenberger, Salina Tsai, Rosalyn A Juergens, Suzanne L Topalian, Charles M Rudin, Malcolm V Brock, Drew Pardoll, and Stephen B Baylin. 2013. “Alterations of Immune Response of Non-Small Lung Cancer with Azacytidine.” ONCOTARGET 4 (11): 2067–2079.
Vancouver
1.
Wrangle J, Wang W, Koch A, Easwaran H, Mohammad HP, Vendetti F, et al. Alterations of immune response of non-small lung cancer with azacytidine. ONCOTARGET. 2013;4(11):2067–79.
IEEE
[1]
J. Wrangle et al., “Alterations of immune response of non-small lung cancer with azacytidine,” ONCOTARGET, vol. 4, no. 11, pp. 2067–2079, 2013.
@article{4174440,
  abstract     = {{Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.}},
  author       = {{Wrangle, John and Wang, Wei and Koch, Alexander and Easwaran, Hariharan and Mohammad, Helai P and Vendetti, Frank and Van Criekinge, Wim and De Meyer, Tim and Du, Zhengzong and Parsana, Princy and Rodgers, Kristen and Yen, Ray-Whay and Zahnow, Cynthia A and Taube, Janis M and Brahmer, Julie R and Tykodi, Scott S and Easton, Keith and Carvajal, Richard D and Jones, Peter A and Laird, Peter W and Weisenberger, Daniel J and Tsai, Salina and Juergens, Rosalyn A and Topalian, Suzanne L and Rudin, Charles M and Brock, Malcolm V and Pardoll, Drew and Baylin, Stephen B}},
  issn         = {{1949-2553}},
  journal      = {{ONCOTARGET}},
  keywords     = {{azacytidine,HDAC inhibitor,non-small cell lung cancer (nsclc),SET ENRICHMENT ANALYSIS,DEMETHYLATING AGENTS,INNATE IMMUNITY,TUMOR ESCAPE,DNA,EXPRESSION,GENES,INTERFERON,METHYLTRANSFERASE,IMMUNOTHERAPY}},
  language     = {{eng}},
  number       = {{11}},
  pages        = {{2067--2079}},
  title        = {{Alterations of immune response of non-small lung cancer with azacytidine}},
  volume       = {{4}},
  year         = {{2013}},
}
Web of Science
Times cited: