Abundant PD-L1 expression in Epstein-Barr Virus-infected gastric cancers

Abstract

// Sarah Derks 1, 2 , Xiaoyun Liao 1, 3, * , Anna M. Chiaravalli 4, * , Xinsen Xu 1 , M. Constanza Camargo 5 , Enrico Solcia 6 , Fausto Sessa 4 , Tania Fleitas 1, 7 , Gordon J. Freeman 1 , Scott J. Rodig 3, 8 , Charles S. Rabkin 5 , Adam J. Bass 1, 9 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 * These authors are contributed equally to this work Correspondence to: Adam J. Bass, email: adam_bass@dfci.harvard.edu 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 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.