title: Overexpression and gene amplification of PD-L1 in cancer cells and PD-L1+immune cells in Epstein-Barr virus-associated gastric cancer: the prognostic implications.
abstract: Cancer cells use PD-L1 to evade antitumor immunity through interaction with programmed cell death protein 1 (PD-1) on T cells. Recent whole-genome sequence studies revealed frequent gene amplification of PD-L1 in Epstein-Barr virus-associated gastric cancer (EBVaGC). To investigate the significance of PD-L1 in cancer cells and their microenvironment in EBVaGC, we studied PD-L1 expression by analysis of the public database and immunohistochemistry with fluorescent in situ hybridization (FISH) of the PD-L1 gene. Analysis of the database from The Cancer Genome Atlas also disclosed high expression of PD-L1 in EBVaGC compared with other molecular subtypes of GC. Expression of PD-L1 was frequently detected in cancer cells of EBVaGC (33/96; 34%), with infiltration of PD-L1+immune cells in its stroma (43/96; 45%). Both expression of PD-L1 in cancer cells and PD-L1+immune cell infiltration in EBVaGC were significantly correlated with diffuse histology according to Lauren's classification and tumor invasion (pT1b or more). As a prognostic indicator, PD-L1 expression in cancer cells correlated with poor outcomes in both overall survival and disease-specific survival (P=0.0498, 0.007). PD-L1-positive cancers had dense infiltration of PD-L1+immune cells as well as CD8+and PD-1+cells in EBVaGC. FISH analysis of representative samples of the tumor demonstrated gene amplification of PD-L1 in 11% of cases. PD-L1-amplified cells corresponded to PD-L1-positive cells showing high-intensity immunohistochemical staining among cancer cells showing weak or moderate intensities. Taken together, PD-L1 expression in cancer cells and their microenvironment may contribute to the progression of EBVaGC, and gene amplification occurs as clonal evolution during progression. This specific subtype of GC infected with EBV is potentially a good candidate for immunotherapy targeting of the PD-L1/PD-1 axis.
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Ruri
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Abe
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kunita
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Hiroharu
authors.initials: H
authors.lastname: Yamashita
authors.affiliation: Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seto
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.|Department of Pathology, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Fukayama
mesh_terms: D000368:Aged; D060890:B7-H1 Antigen / Q000235:genetics*; D018450:Disease Progression; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D004854:Herpesvirus 4, Human / Q000302:isolation & purification*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology / Q000821:virology; D059016:Tumor Microenvironment
chemical_list: D060890:B7-H1 Antigen; C423236:CD274 protein, human