The Role of EBV-Encoded LMP1 in the NPC Tumor Microenvironment: From Function to Therapy

Abstract

Nasopharyngeal carcinoma (NPC) is closely associated with Epstein-Barr virus (EBV) infection. It is also characterized by heavy infiltration with non-malignant leucocytes. The EBV-encoded latent membrane protein 1 (LMP1) is believed to play an important role in NPC pathogenesis by virtue of its ability to activate multiple cell signaling pathways which collectively promote cell proliferation and survival, angiogenesis, invasiveness, and aerobic glycolysis. LMP1 also affects cell-cell interactions, antigen presentation, and cytokine and chemokine production. Here, we discuss how LMP1 modulates local immune responses that contribute to the establishment of the NPC tumor microenvironment. We also discuss strategies for targeting the LMP1 protein as a novel therapy for EBV-driven malignancies.

Keywords: Epstein-Barr virus; latent membrane protein 1; nasopharyngeal carcinoma; therapy; tumor microenvironment.

Figure 1

Activation of multiple cell signaling pathways by LMP1 promotes cell survival, proliferation, angiogenesis, invasion, metastasis, and cytokine production.

Figure 2

The NPC immune microenvironment. Schematic illustrating the induction of NF-κB and STAT3 signaling pathways and multiple immune cytokines by LMP1 in cancer cells resulting in cancer cell growth, angiogenesis, EMT, migration and invasion as well as chemotaxis of lymphocytes, NK cells, macrophage (Mφ), neutrophil, MDSC, Tregs, to the tumor site. The presence of TGFβ and IL-10, along with the LMP1 upregulation of PDL-1 and PD-1, and the release of LMP1-containing exosomes into the tumor TME to induce expansion of Tregs, MDSC and TAM, which create an immunosuppressive TME that facilitates tumor evasion.