title: Alterations of immune response of Non-Small Cell Lung Cancer with Azacytidine.
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.
authors.affiliation: The Johns Hopkins University, School of Medicine, Oncology Center-Hematology/Medical Oncology, Baltimore, Maryland.
authors.forename: John
authors.initials: J
authors.lastname: Wrangle
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Alexander
authors.initials: A
authors.lastname: Koch
authors.forename: Hariharan
authors.initials: H
authors.lastname: Easwaran
authors.forename: Helai P
authors.initials: HP
authors.lastname: Mohammad
authors.forename: Frank
authors.initials: F
authors.lastname: Vendetti
authors.forename: Wim
authors.initials: W
authors.lastname: Vancriekinge
authors.forename: Timothy
authors.initials: T
authors.lastname: Demeyer
authors.forename: Zhengzong
authors.initials: Z
authors.lastname: Du
authors.forename: Princy
authors.initials: P
authors.lastname: Parsana
authors.forename: Kristen
authors.initials: K
authors.lastname: Rodgers
authors.forename: Ray-Whay
authors.initials: RW
authors.lastname: Yen
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Zahnow
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.forename: Julie R
authors.initials: JR
authors.lastname: Brahmer
authors.forename: Scott S
authors.initials: SS
authors.lastname: Tykodi
authors.forename: Keith
authors.initials: K
authors.lastname: Easton
authors.forename: Richard D
authors.initials: RD
authors.lastname: Carvajal
authors.forename: Peter A
authors.initials: PA
authors.lastname: Jones
authors.forename: Peter W
authors.initials: PW
authors.lastname: Laird
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Weisenberger
authors.forename: Salina
authors.initials: S
authors.lastname: Tsai
authors.forename: Rosalyn A
authors.initials: RA
authors.lastname: Juergens
authors.forename: Suzanne L
authors.initials: SL
authors.lastname: Topalian
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Malcolm V
authors.initials: MV
authors.lastname: Brock
authors.forename: Drew
authors.initials: D
authors.lastname: Pardoll
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001374:Azacitidine / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects; D057890:Epigenomics; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D015398:Signal Transduction; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000964:Antimetabolites, Antineoplastic; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D001374:Azacitidine