Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine. Academic Article uri icon

Overview

MeSH

  • Antigens, CD274
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenomics
  • Humans
  • Programmed Cell Death 1 Receptor
  • Signal Transduction
  • Up-Regulation

MeSH Major

  • Antimetabolites, Antineoplastic
  • Azacitidine
  • Carcinoma, Non-Small-Cell Lung
  • Immunotherapy
  • Lung Neoplasms

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.

publication date

  • November 2013

has subject area

  • Antigens, CD274
  • Antimetabolites, Antineoplastic
  • Azacitidine
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • DNA Methylation
  • Epigenomics
  • Humans
  • Immunotherapy
  • Lung Neoplasms
  • Programmed Cell Death 1 Receptor
  • Signal Transduction
  • Up-Regulation

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3875770

Digital Object Identifier (DOI)

  • 10.18632/oncotarget.1542

PubMed ID

  • 24162015

Additional Document Info

start page

  • 2067

end page

  • 2079

volume

  • 4

number

  • 11