title: Differential Expression and Significance of PD-L1, IDO-1, and B7-H4 in Human Lung Cancer.
abstract: OBJECTIVE
  To determine the expression level, associations, and biological role of PD-L1, IDO-1, and B7-H4 in non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Using multiplexed quantitative immunofluorescence (QIF), we measured the levels of PD-L1, IDO-1, B7-H4, and different tumor-infiltrating lymphoycte (TIL) subsets in 552 stages I-IV lung carcinomas from two independent populations. Associations between the marker levels, TILs, and major clinicopathologic variables were determined. Validation of findings was performed using mRNA expression data from The Cancer Genome Atlas (TCGA) and in vitro stimulation of lung adenocarcinoma A549 cells with IFNγ and IL10.
  
  
  RESULTS
  PD-L1 was detected in 16.9% and 21.8% of cases in each population. IDO-1 was expressed in 42.6% and 49.8%; and B7-H4 in 12.8% and 22.6% of cases, respectively. Elevated PD-L1 and IDO-1 were consistently associated with prominent B- and T-cell infiltrates, but B7-H4 was not. Coexpression of the three protein markers was infrequent, and comparable results were seen in the lung cancer TCGA dataset. Levels of PD-L1 and IDO-1 (but not B7-H4) were increased by IFNγ stimulation in A549 cells. Treatment with IL10 upregulated B7-H4 but did not affect PD-L1 and IDO-1 levels.
  
  
  CONCLUSIONS
  PD-L1, IDO-1, and B7-H4 are differentially expressed in human lung carcinomas and show limited co-expression. While PD-L1 and IDO-1 are associated with increased TILs and IFNγ stimulation, B7-H4 is not. The preferential expression of discrete immune evasion pathways in lung cancer could participate in therapeutic resistance and support design of optimal clinical trials. Clin Cancer Res; 23(2); 370-8. ©2016 AACR.
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut. kurt.schalper@yale.edu.|Medical Oncology Section, Yale School of Medicine, New Haven, Connecticut.|Translational Immuno-oncology Laboratory, Yale Cancer Center, New Haven, Connecticut.
authors.forename: Kurt A
authors.initials: KA
authors.lastname: Schalper
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Daniel
authors.initials: D
authors.lastname: Carvajal-Hausdorf
authors.affiliation: Medical Oncology Section, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Joseph
authors.initials: J
authors.lastname: McLaughlin
authors.affiliation: Medical Oncology Section, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Altan
authors.affiliation: Solid Tumor Oncology, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Vamsidhar
authors.initials: V
authors.lastname: Velcheti
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Patricia
authors.initials: P
authors.lastname: Gaule
authors.affiliation: Immunobiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Miguel F
authors.initials: MF
authors.lastname: Sanmamed
authors.affiliation: Immunobiology, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Lieping
authors.initials: L
authors.lastname: Chen
authors.affiliation: Medical Oncology Section, Yale School of Medicine, New Haven, Connecticut.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.affiliation: Department of Pathology, Yale School of Medicine, New Haven, Connecticut.|Medical Oncology Section, Yale School of Medicine, New Haven, Connecticut.
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
mesh_terms: D000072283:A549 Cells; D000368:Aged; D060890:B7-H1 Antigen / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D007371:Interferon-gamma / Q000494:pharmacology; D016753:Interleukin-10 / Q000494:pharmacology; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology; D008875:Middle Aged; D009367:Neoplasm Staging; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000235:genetics*
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D012333:RNA, Messenger; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C475826:VTCN1 protein, human; D016753:Interleukin-10; D007371:Interferon-gamma