title: Programmed Death-Ligand 1 Expression Is Common in Gastric Cancer Associated With Epstein-Barr Virus or Microsatellite Instability.
abstract: Blockade of the programmed death 1 (PD-1) pathway has emerged as a novel therapy for cancer. Therefore, development of biomarkers for response prediction, such as PD-ligand 1 (PD-L1) expression by immunohistochemistry, may help to stratify patients. Solid tumors with CD8 T-cell rich tumor microenvironment have been implicated to be associated with increased PD-L1 expression. We hypothesized that gastric cancers associated with Epstein-Barr virus infection (EBV+) or microsatellite instability (MSI), both of which are known to harbor such tumor microenvironment, are associated with increased PD-L1 expression. Forty-four resected gastric cancers including 7 EBV+, 16 MSI, and 21 microsatellite stable cancers without EBV (EBV-/MSS) were studied for PD-L1 expression and T-cell subpopulations by immunohistochemistry. Positive PD-L1 expression (PD-L1+), defined as membranous staining in either tumor cells or tumor immune infiltrates, was seen in 32 (72%) gastric cancers. EBV+ or MSI cancers showed significantly higher rates of PD-L1+ compared with EBV-/MSS cancers (7/7, 100%; 14/16, 87%; 11/21, 52%; P=0.013). PD-L1+/EBV+ and PD-L1+/MSI cancers had significantly more CD8 T cells at tumor invasive front than PD-L1+/EBV-/MSS cancers (P<0.001). PD-L1+ was not associated with the depth of invasion or nodal metastasis (P=0.534, 0.288). Multivariate analysis showed PD-L1+ was not an independent predictor of disease-free survival while MSI was (P=0.548, 0.043). In summary, EBV+ or MSI gastric cancers are more likely to express PD-L1 and have increased CD8 T cells at tumor invasive front than EBV-/MSS cancers. Our results suggest EBV infection and MSI should be investigated for predicting response to PD-1 blockade.
authors.affiliation: Departments of *Pathology †Medicine, Division of Hematology Oncology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Changqing
authors.initials: C
authors.lastname: Ma
authors.forename: Krishna
authors.initials: K
authors.lastname: Patel
authors.forename: Aatur D
authors.initials: AD
authors.lastname: Singhi
authors.forename: Bing
authors.initials: B
authors.lastname: Ren
authors.forename: Benjamin
authors.initials: B
authors.lastname: Zhu
authors.forename: Fyza
authors.initials: F
authors.lastname: Shaikh
authors.forename: Weijing
authors.initials: W
authors.lastname: Sun
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000096:biosynthesis*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018572:Disease-Free Survival; D020031:Epstein-Barr Virus Infections / Q000150:complications*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology*; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D016016:Proportional Hazards Models; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology / Q000821:virology
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human