title: Significance of immune checkpoint proteins in EGFR-mutant non-small cell lung cancer.
abstract: To characterize the expression of PD-L1, PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and T-cell immunoglobulin and mucin-domain containing-3 (TIM3) in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC).
  
  
  
  Samples from 90 patients with newly diagnosed advanced stage NSCLC harboring EGFR mutations and treated with first line EGFR tyrosine kinase inhibitors (TKI) within 3 months of diagnosis were stained for CTLA-4, PD-L1, PD-1, TIM-3 and CD3 expression by immunohistochemistry.
  
  
  
  PD-L1 was present in at least 1% of immune and tumor cells in 44% and 59% of samples, respectively. In multivariate analysis, increased CD3 immune shaped cell (ISC) counts (HR 2.805, p=0.034) and high PD-L1 tumor H-score (HR 3.805, p=0.022) was associated with a shorter progression free survival and high CTLA-4 ISC counts was associated with borderline overall survival significance (HR 1.054, p=0.061).
  
  
  
  Tumor PD-L1 expression was significantly associated with a shorter PFS whereas immune cell CTLA-4 may be prognostic for OS. Our findings support the ongoing development of CTLA-4 and PD1/PD-L1 inhibitors in this important molecularly defined subset of lung adenocarcinoma.
authors.affiliation: Department of Haematology-Oncology, National University Cancer Institute, Singapore, National University Health System, Singapore; School of Surgery, University of Western Australia, Perth, Australia; Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. Electronic address: ross_soo@nuhs.edu.sg.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Soo
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea.
authors.forename: Hye Ryun
authors.initials: HR
authors.lastname: Kim
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Bernadette Reyna
authors.initials: BR
authors.lastname: Asuncion
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Zul
authors.initials: Z
authors.lastname: Fazreen
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Mohamed Feroz Mohd
authors.initials: MFM
authors.lastname: Omar
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Maria Cynthia
authors.initials: MC
authors.lastname: Herrera
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Joey Sze
authors.initials: JS
authors.lastname: Yun Lim
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Grace
authors.initials: G
authors.lastname: Sia
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Richie
authors.initials: R
authors.lastname: Soong
authors.affiliation: Division of Medical Oncology, Yonsei Cancer Center, Seoul, South Korea.
authors.forename: Byoung-Chul
authors.initials: BC
authors.lastname: Cho
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D017252:CD3 Complex / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D066246:ErbB Receptors / Q000235:genetics*; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2 / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage* / Q000627:therapeutic use; D016019:Survival Analysis; D016896:Treatment Outcome
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: Cytotoxic T-lymphocyte antigen-4; Epidermal growth factor receptor mutations; Non-small cell lung cancer; Programmed death ligand-1; T-cell immunoglobulin and mucin-domain containing-3