Revealing the crosstalk between nasopharyngeal carcinoma and immune cells in the tumor microenvironment

Abstract

Nasopharyngeal carcinoma (NPC) arises from the epithelial cells located in the nasopharynx and has a distinct geographic distribution. Chronic Epstein-Barr virus (EBV) infection, as its most common causative agents, can be detected in 100% of NPC types. In-depth studies of the cellular and molecular events leading to immunosuppression in NPC have revealed new therapeutic targets and diverse combinations that promise to benefit patients with highly refractory, advanced and metastatic NPC. This paper reviews the mechanisms by which NPC cells to circumvent immune surveillance and approaches being attempted to restore immunity. We integrate existing insights into anti-NPC immunity and molecular signaling pathways as well as targeting therapies in anticipation of broader applicability and effectiveness in advanced metastatic NPC.

Keywords: Immune cell; Immunotherapy; Nasopharyngeal carcinoma; Tumor microenvironment.

Fig. 1

Mechanisms of immune escape in nasopharyngeal carcinoma. EBV-encoding miRNA mediates the escape of the NK cell killing by down-regulating the expression of ligands to NKG2D. NPC cells also secrete factors such as TGF-β to inhibits the recruitment of APCs, and meanwhile, secret several chemokines to recruit immunosuppressive regulatory T cells (Treg). Tregs further inhibit the function of APCs through the binding of CTLA-4 to CD86 and releases suppressive cytokines such as IL-10 to activated effector T cells (Teff), prohibiting their cytotoxicity to NPC. Its expression of membrane-bound TGF-β also inhibits the action of NKs. NPC cells directly inhibit the action of Teff by expressing PD-L1 ligand, which induce T cell anergy upon binding to PD-1. Secretion of exosomes containing LMP1, miRNA, Galectin1 and Galectin 9 leads to disfunction of Teff and NK

Fig. 2

Pathways of exosomes involved in NPC immunosuppression. NPC affects the activities of immune effector cells by secreting exosomes to maintain persistent EBV infection and cause immunosuppression

Fig. 3

Aerobic glycolysis in NPC cells. LMP1 secreted by EBV enhances glucose consumption and lactate generation in NPC cells. Increased glucose consumption in the tumor cells leads to immune cell starvation. EBV (LMP1) leads to the accumulation of fumarate in the tricarboxylic acid cycle (TCA), which inhibits the expression of RIP3 and protects NPC cells from TNF-induced necrotizing apoptosis. GLUT1: glucose transporter 1, OAA: Oxaloacetic acid, a-KG: a–ketoglutarate, LDH: lactate dehydrogenase, G6PD: glucose-6-phosphate dehydrogenase