Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers
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Sarah Derks1,2, Xiaoyun Liao1,3,*, Anna M. Chiaravalli4,*, Xinsen Xu1, M. Constanza Camargo5, Enrico Solcia6, Fausto Sessa4, Tania Fleitas1,7, Gordon J. Freeman1, Scott J. Rodig3,8, Charles S. Rabkin5, Adam J. Bass1,9
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
2Department of Medical Oncology, VU University Medical Center, Amsterdam, The Netherlands
3The Center for Immuno-Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
4Department of Pathology, Ospedale di Circolo, Varese, Italy
5Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland, USA
6Department of Molecular Medicine, University of Pavia and Policlinico S. Matteo, Pavia, Italy
7Department of Medical Oncology, Hospital Clínico Universitario de Valencia, Valencia, Spain
8Department of Pathology, Brigham and Women’s Hospital, Boston, Massachusetts, USA
9Cancer Program, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
*These authors are contributed equally to this work
Adam J. Bass, email: [email protected]
Keywords: EBV-infected gastric cancers, MSI gastric cancer, PD-L1, PD-1 inhibitors
Received: February 01, 2016 Accepted: April 10, 2016 Published: April 28, 2016
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.
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