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.

Heterogeneity in Gastric Cancer: From Pure Morphology to Molecular Classifications

“…Several studies have demonstrated that PD-L1 immunoexpression is heterogeneous in GC, as in other tumour models. PD-L1 overexpression is associated with high densities of CD3+ and CD8+ tumour-infiltrating lymphocytes [67][68][69], GC with lymphoid stroma morphology [70], and both an EBV+ and MSI-high molecular status [69,[71][72][73][74]. However, the correlation with PD-L1 amplification, prognosis, and response to targeted immunotherapies is still debated and deserves further study.…”

Immunotherapy of Esophageal Cancer: Current Status, Many Trials and Innovative Strategies

“…The expression of PD-L1 significantly increases in both tumor and stromal cells in the EBV and MSI subtype [45]. Herein, a high expression of PD-L1 might predict a better response to neoadjuvant chemotherapy in EAC, and it is associated with a higher pathological response [46].…”

Immune Checkpoint Inhibition in Gastro-Oesophageal Cancer

“…These subtypes demonstrate diversity in immunological targets, with EBV and MSI subtypes the most promising in this regard. Amplification of 9p encoding PD-L1 and PD-L2 genes is often found in EBV-positive tumours, and high levels of PD-L1 protein expression has been demonstrated on tumour cells in EBV-positive gastric adenocarcinoma [43]. Germline or acquired defects in mismatch repair processes lead to high levels of mutations and neo-antigen presentation in MSI gastric cancer, which in turn leads to tumour-infiltrating lymphocyte invasion and PD-L1 expression [44,45].…”

“…Germline or acquired defects in mismatch repair processes lead to high levels of mutations and neo-antigen presentation in MSI gastric cancer, which in turn leads to tumour-infiltrating lymphocyte invasion and PD-L1 expression [44,45]. Both EBV and MSI gastric adenocarcinoma have high levels expression of gene signatures which are associated with response to PD-1 therapy [22,43]. However, although EBV and MSI gastric cancer may be more likely to benefit from immunotherapy, because of their innate positive prognostic value, these subtypes are less often found in patients with advanced disease than other subtypes.…”