title: Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers.
abstract: Gastric cancer (GC) is a deadly disease with limited treatment options. Recent studies with PD-1 inhibition have shown promising results in GC, but key questions remain regarding which GC subclass may respond best. In other cancers, expression of the PD-1 ligand PD-L1 has been shown to identify cancers with greater likelihood of response to PD-1 blockade. We here show with immunohistochemistry that Epstein-Barr Virus (EBV)+ GCs (n = 32) have robust PD-L1 expression not seen in other GCs. In EBV+ GC, we observed PD-L1 staining in tumor cells in 50% (16/32) and immune cells in 94% (30/32) of cases. Among EBV-negative GCs, PD-L1 expression within tumors cells was observed only in cases with microsatellite instability (MSI), although 35% of EBV-/MSS GCs possessed PD-L1 expression of inflammatory cells. Moreover, distinct classes of GC showed different patterns of PD-L1+ immune cell infiltrations. In both EBV+ and MSI tumors, PD-L1+ inflammatory cells were observed to infiltrate the tumor. By contrast, such cells remained at the tumor border of EBV-/MSS GCs. Consistent with these findings, we utilized gene expression profiling of GCs from The Cancer Genome Atlas study to demonstrate that an interferon-γ driven gene signature, an additional proposed marker of sensitivity to PD-1 therapy, were enriched in EBV+ and MSI GC. These data suggest that patients with EBV+ and MSI GC may have greater likelihood of response to PD-1 blockade and that EBV and MSI status should be evaluated as variables in clinical trials of these emerging inhibitors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Sarah
authors.initials: S
authors.lastname: Derks
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Liao
authors.affiliation: Department of Pathology, Ospedale di Circolo, Varese, Italy.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Chiaravalli
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Xinsen
authors.initials: X
authors.lastname: Xu
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
authors.forename: M Constanza
authors.initials: MC
authors.lastname: Camargo
authors.affiliation: Department of Molecular Medicine, University of Pavia and Policlinico S. Matteo, Pavia, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Solcia
authors.affiliation: Department of Pathology, Ospedale di Circolo, Varese, Italy.
authors.forename: Fausto
authors.initials: F
authors.lastname: Sessa
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia, Spain.
authors.forename: Tania
authors.initials: T
authors.lastname: Fleitas
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.affiliation: The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Rabkin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Bass
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D020031:Epstein-Barr Virus Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology*
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human; D007371:Interferon-gamma
keywords: EBV-infected gastric cancers; MSI gastric cancer; PD-1 inhibitors; PD-L1