EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: Implications for oncotargeted therapy

Abstract

PD-L1 expression is a feature of Epstein-Barr virus (EBV) associated malignancies such as nasopharyngeal carcinoma (NPC). Here, we found that EBV-induced latent membrane protein 1 (LMP1) and IFN-γ pathways cooperate to regulate programmed cell death protein 1 ligand (PD-L1). Expression of PD-L1 was higher in EBV positive NPC cell lines compared with EBV negative cell lines. PD-L1 expression could be increased by exogenous and endogenous induction of LMP1 induced PD-L1. In agreement, expression of PD-L1 was suppressed by knocking down LMP1 in EBV positive cell lines. We further demonstrated that LMP1 up-regulated PD-L1 through STAT3, AP-1, and NF-κB pathways. Besides, IFN-γ was independent of but synergetic with LMP1 in up-regulating PD-L1 in NPC. Furthermore, we showed that PD-L1 was associated with worse disease-free survival in NPC patients. These results imply that blocking both the LMP1 oncogenic pathway and PD-1/PD-L1 checkpoints may be a promising therapeutic approach for EBV positive NPC patients.

Programmed Death-Ligand 1 Expression, Microsatellite Instability, Epstein–Barr Virus, and Human Papillomavirus in Nasopharyngeal Carcinomas of Patients from the Philippines

“…The in vitro findings suggest that EBV infection may happen first in the pathogenesis of NPC and MSI can be induced by EBV. In addition, our results confirm findings of other studies [14][15][16][17] that positive PD-L1 expression is frequent in NPCs, but is not associated with clinicopathologic parameters. Although it was previously reported as an independent predictor of survival [16], in our cohort from the Philippines, positive PD-L1 expression was not associated with OS.…”

“…PD-L1 expression was described in other EBV-associated malignancies [11][12][13] and several studies have reported positive PD-L1 expression in 25-89% of NPCs [14][15][16][17]. In contrast to EBV-associated gastric adenocarcinomas in which expression of PD-L1 protein may result from PD-L1 gene amplification [18], NPCs do not have PD-L1 gene copy number change [19].…”

“…In contrast to EBV-associated gastric adenocarcinomas in which expression of PD-L1 protein may result from PD-L1 gene amplification [18], NPCs do not have PD-L1 gene copy number change [19]. PD-L1 expression is shown to be associated with either constitutive oncogenic activation mediated by EBV-encoded latent-membrane protein 1, or through interferon-c signaling pathways [16].…”

“…PD-L1 expression has also been associated with overall survival (OS) and disease-free/progression-free survival (DFS/PFS) mostly in Chinese ''NPC'' patients [15][16][17]. Fang et al [16] reported that positive PD-L1 expression in NPCs was not associated with pT, pN, or clinical stage but was an independent prognostic factor for DFS in a patient cohort collected from Guangzhou, China.…”

“…Fang et al [16] reported that positive PD-L1 expression in NPCs was not associated with pT, pN, or clinical stage but was an independent prognostic factor for DFS in a patient cohort collected from Guangzhou, China. In contrast, Hsu and colleagues reported that in NPC patients from Taiwan, PD-L1 expression was not associated with either OS or DFS [15].…”