title: Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma.
abstract: Recent data supports a significant role for immune checkpoint inhibitors in the treatment of solid tumours. Here, we evaluate gastric and gastro-oesophageal junction (G/GEJ) adenocarcinomas for their expression of programmed death-ligand 1 (PD-L1), infiltration by CD8+ T cells and the relationship of both factors to patient survival.
  
  
  
  Thirty-four resections of primary invasive G/GEJ were stained by immunohistochemistry for PD-L1 and CD8 and by DNA in situ hybridisation for Epstein-Barr virus (EBV). CD8+ T cell densities both within tumours and at the tumour-stromal interface were analysed using whole slide digital imaging. Patient survival was evaluated according to PD-L1 status and CD8 density.
  
  
  
  12% of resections showed tumour cell membranous PD-L1 expression and 44% showed expression within the immune stroma. Two cases (6%) were EBV positive, with one showing membranous PD-L1 positivity. Increasing CD8+ densities both within tumours and immune stroma was associated with increasing percentage of tumour (p=0.027) and stromal (p=0.005) PD-L1 expression. Both tumour and immune stromal PD-L1 expression and high intratumoral or stromal CD8+ T cell density (>500/mm2) were associated with worse progression-free survival (PFS) and overall survival (OS).
  
  
  
  PD-L1 is expressed on both tumour cells and in the immune stroma across all stages and histologies of G/GEJ. Surprisingly, we demonstrate that increasing CD8 infiltration is correlated with impaired PFS and OS. Patients with higher CD8+ T cell densities also have higher PD-L1 expression, indicating an adaptive immune resistance mechanism may be occurring. Further characterisation of the G/GEJ immune microenvironment may highlight targets for immune-based therapy.
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Thompson
authors.affiliation: Division of Biostatistics and Bioinformatics, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Murphy
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Toby
authors.initials: T
authors.lastname: Cornish
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Cuka
authors.affiliation: Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Eihab
authors.initials: E
authors.lastname: Abdelfatah
authors.affiliation: Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Duncan
authors.affiliation: Department of Surgery, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Nita
authors.initials: N
authors.lastname: Ahuja
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.|Department of Dermatology, The Johns Hopkins Hospital, Baltimore Maryland, USA.
authors.forename: Janis M
authors.initials: JM
authors.lastname: Taube
authors.affiliation: Department of Pathology, The Johns Hopkins Hospital, Baltimore, Maryland, USA.|Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Department of Oncology, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins Hospital, Baltimore, Maryland, USA.
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
mesh_terms: D000230:Adenocarcinoma / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000821:virology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000032:analysis* / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D004279:DNA, Viral / Q000032:analysis*; D018572:Disease-Free Survival; D004943:Esophagogastric Junction / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000821:virology; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D013274:Stomach Neoplasms / Q000737:chemistry* / Q000276:immunology / Q000473:pathology / Q000821:virology; D015996:Survival Rate; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D004279:DNA, Viral
keywords: CANCER IMMUNOBIOLOGY; GASTRIC CANCER; IMMUNE RESPONSE; IMMUNOTHERAPY