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.

Journal

Journal ID (nlm-ta): Oncotarget

Journal ID (iso-abbrev): Oncotarget

Journal ID (publisher-id): Oncotarget

Journal ID (publisher-id): ImpactJ

Title: Oncotarget

Publisher: Impact Journals LLC

ISSN (Electronic): 1949-2553

Publication date Collection: 31 May 2016

Publication date (Electronic): 28 April 2016

Volume: 7

Issue: 22

Pages: 32925-32932

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

² Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands

³ The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA

⁴ Department of Pathology, Ospedale di Circolo, Varese, Italy

⁵ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA

⁶ Department of Molecular Medicine, University of Pavia and Policlinico S. Matteo, Pavia, Italy

⁷ Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia, Spain

⁸ Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA

⁹ Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA

Author notes

Correspondence to: Adam J. Bass, adam_bass@ 123456dfci.harvard.edu

Article

Publisher ID: 9076

DOI: 10.18632/oncotarget.9076

PMC ID: 5078063

PubMed ID: 27147580

Copyright statement: Copyright: © 2016 Derks et al.

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Categories

Subject: Research Paper