Metabolic Reprogramming and Immune Evasion in Nasopharyngeal Carcinoma

Abstract

Nasopharyngeal carcinoma (NPC) is a malignant tumor of the nasopharynx mainly characterized by geographic distribution and EBV infection. Metabolic reprogramming, one of the cancer hallmarks, has been frequently reported in NPCs to adapt to internal energy demands and external environmental pressures. Inevitably, the metabolic reprogramming within the tumor cell will lead to a decreased pH value and diverse nutritional supplements in the tumor-infiltrating micro-environment incorporating immune cells, fibroblasts, and endothelial cells. Accumulated evidence indicates that metabolic reprogramming derived from NPC cells may facilitate cancer progression and immunosuppression by cell-cell communications with their surrounding immune cells. This review presents the dysregulated metabolism processes, including glucose, fatty acid, amino acid, nucleotide metabolism, and their mutual interactions in NPC. Moreover, the potential connections between reprogrammed metabolism, tumor immunity, and associated therapy would be discussed in this review. Accordingly, the development of targets on the interactions between metabolic reprogramming and immune cells may provide assistances to overcome the current treatment resistance in NPC patients.

Keywords: immune cell; immunotherapy; metabolism; nasopharyngeal carcinoma; pH.

Figure 1

Aerobic glycolysis of NPC cell. GLUT1 expression is up-regulated and glucose uptake is increased. The expression level of HK is increased and promotes glycolysis. PKM2 over-expression promotes GLUT1 expression and glucose absorption. The expression of PDHB is down-regulated, which inhibits the conversion of pyruvate to acetyl CoA. PDK1 is highly expressed, which leads to the inactivation of PDHB. The over-expression of IDH2 promoted the transformation of α - KG to 2-HG. LDH expression and lactate production increased. EBV secreted-protein LMP1 promotes glucose uptake and lactate production. In pentose phosphate pathway, EBV-miR-BART1 promotes G6PD over-expression. GLUT1: glucose transporter 1, HK: hexokinase, PKM2: pyruvate kinase M2, PDHB: pyruvate dehydrogenase B, PDK1: pyruvate dehydrogenase kinase 1, IDH2: isocitrate dehydrogenase, α-KG: α–ketoglutarate, 2-HG: 2-hydroxyglutaric acid, LDH: lactate dehydrogenase, LMP1: EBV latent membrane protein 1, BART1: EBV-encoded microRNA BART1, G6PD: glucose-6-phosphate dehydrogenase.

Figure 2

Fatty acid metabolism of NPC cell. LMP2A down-regulates lipolysis gene ATGL and promotes fat droplet accumulation; CD36 transports fatty acid to the cytoplasm. ME1 enhances malate pyruvate cycle, promotes transfer of acetyl CoA from mitochondria to cytoplasm, and participates in palmitic acid synthesis. FASN is up-regulated expression and palmitic acid synthesis is vigorous. CPT1A is positively regulated by PROX1、SOD1、PGC1α and MAGL. Inactivation of HMGCL inhibits ketone like β-HB metabolism of fatty acid and reduced production of ROS. LMP2A: EBV encoded latent membrane protein 2A, ATGL: adipotriglyceride lipase, CD36: fatty acid translocase, ME1: malic enzyme 1, FASN: fatty acid synthase, CPT1A: carnitine acyltransferase 1, PROX1: Prospero homeobox protein-1, SOD1: superoxide dismutase 1, PGC1α: peroxisome proliferator-activated receptor coactivator 1, MAGL: monoacylglycerol lipase, HMGCL: HMG-CoA lyase, β-HB: β-hydroxybutyric acid,ROS: reactive oxygen species.

Figure 3

Amino acid metabolism of NPC cell. GLS promotes the combination of glutamate and amino groups to produce glutamine, which not only supplies energy but also scavenges ammonia. The expression of KGA and GAC subtypes are increased, and GLUD1 and GLUD2 are also up-regulated and promote the decomposition of glutamine and glutamic acid and produced more ammonia and α – ketoglutarate. This provides raw materials for energy generation and biosynthesis. ASS1 is down-regulated, which inhibited the ornithine cycle. GLS: glutamine synthetase, KGA: K-glutaminase GAC: glutaminase C, GLUD1: glutamate dehydrogenase 1, GLUD2: glutamate dehydrogenase 2, CPS: carbamoyl phosphate, ARSA: arginine succinate, ASS1: arginine succinate synthase, BCAA: branched-chain amino acid.

Figure 4

The landscape of key metabolic gene mutations, variants and copy number alternations in NPC and other head and neck cancer from cBioPortal (https://www.cbioportal.org/).

Figure 5

The immune evasion mechanism of NPC cell. C15 exosomes induced transformation and aggregation of CD4+CD25+Treg cells. NF-κB regulates a variety of chemokines CXCL9, CXCL10, CX3CL1, and CCL20 to reshape the tumor immune microenvironment. TRIM29 blocks interferon production. Galectin-9/Tim3 can induce apoptosis of CD4 T cells and inhibit Th1. LMP2A changes HLA-I, block recognition and presentation of cancer cell antigen peptide, and inhibit killing effect of NK cells. EBV-related products, such as BZLF1, EBERS AND BARF1, inhibit IFN - γ and IFN - α to escape immune clearance, respectively. LMP1 inhibits the differentiation of B cells into antibody-secreting cells. Some microRNAs of EBV down-regulate immune ligand MICB, which hinders recognition of NK cells.C15:C15 exosomes, CXCL9, CXCL10, CX3CL1, CCL20: chemokines of different subfamilies, TRIM29: EBV-induced tripartite motif-containing 29 protein, LMP2A: EBV latent membrane protein 2A, HLA-I: human leukocyte antigen I, BZLF1, EBERs, BARF1:EBV-related production, LMP1: EBV latent membrane protein 1, MICB: MHC class I chain-related MIC.

Figure 6

Effects of metabolites derived from tumor cells on immune cells and nutritional competition between cancer cells and immune cells. Tumor cells have competitive advantages over glutamine and glucose. Tumor cells produce a lot of lactate, which is transported to extracellular environment. High concentration of lactate hinders transfer of lactate from T cells and interferes with metabolism and function of T cells. Lactate damages dendritic cells and inhibits monocyte migration and cytokine release. Lactate inhibits the effect of TNF. In tumor microenvironment, tryptophan is decreased, while kynurenine and tryptophan is increased. IDO is highly expressed in tumor cells and catalyzes tryptophan degradation. Tryptophan is metabolized to produce kynurenine, which promotes the differentiation of CD4 + T cells into Treg cells by activating kynurenine AHR signal axis. IDO also activates Treg cells to up-regulate the expression of PD-L1 and inhibited the proliferation of T cells through PD-1/PD-L1 pathway. M1-TAM decreases but M2- TAM increases. Lactate and MAGL induced M2 like polarization of TAMs. In addition, hyaluronic acid is increased in matrix, and Treg cells are highly expressed. TNF: tumor necrosis factor, IDO: indoleamine 2,3-dioxygenase, AHR pathway: kynurenine aryl hydrocarbon receptor signal axis, TAM: tumor-associated macrophage, M1-TAM: M1 type tumor-associated macrophage, M2-TAM: M2 type tumor-associated macrophage.