Metabolic Traits in Cutaneous Melanoma

Abstract

Tumor microenvironment is a network of complex cellular and molecular systems where cells will gain specific phenotypes and specific functions that would drive tumorigenesis. In skin cancers, tumor microenvironment is characterized by tumor infiltrating immune cells that sustain immune suppression, mainly lymphocytes. Melanoma cellular heterogeneity can be described on genetic, proteomic, transcriptomic and metabolomic levels. Melanoma cells display a metabolic reprogramming triggered by both genetic alterations and adaptation to a microenvironment that lacks nutrients and oxygen supply. Tumor cells present clear metabolic adaptations and identifying deregulated glycolysis pathway could offer new therapy targets. Moreover, the immune cells (T lymphocytes, macrophages, NK cells, neutrophils and so on) that infiltrate melanoma tumors have metabolic particularities that, upon interaction within tumor microenvironment, would favor tumorigenesis. Analyzing both tumor cell metabolism and the metabolic outline of immune cells can offer innovative insights in new therapy targets and cancer therapeutical approaches. In addition to already approved immune- and targeted therapy in melanoma, approaching metabolic check-points could improve therapy efficacy and hinder resistance to therapy.

Keywords: immune cells; melanoma; metabolism; therapy; tumor microenvironment.

Figure 1

Metabolic traits of T cells upon differentiation in activated states. Naïve T cells are characterized by low levels of glucose uptake and cellular energetics is sustained by mitochondrial oxidative phosphorylation (OXPHOS). When cells are activated into effector CD8+ T lymphocytes, mTOR signaling is activated and cells switch to aerobic glycolysis characterizing a short lived cell with high cytotoxic function. When cells are activated into memory cell low glycolytic metabolism and augmented OXPHOS characterizing a cell with medium cytotoxic function, self-renewal capacity and long-lived cell.

Figure 2

Metabolic traits of NK cells and dendritic cells upon differentiation in activated states. (A) NK cells in the resting state have low levels of glucose uptake and OXPHOS metabolism and upon activation there is an increased expression of Glut1R increasing thus the fuel uptake, would increase the expression of transferrin receptor (CD71), receptors for large neutral amino acids (SLC7a5), glutamine (SLC1A5) and for free fatty acid (CD36); all these changes sustain a high cytotoxic activity; (B) Dendritic cells in the resting state rely on pre-stored glycogen, use glycolysis, TCA cycle, when differentiating upon activation in Bone-marrow-derived DCs (BMDCs) increased expression of Glut1R mTOR-HIF-1alpha/NOS leads to aerobic glycolysis that will increase expression of MHC molecules, cytokines and the costimulatory ligands (CD80 and CD86); classical dendritic cells (cDC) would use the autocrine IFN activation to enhance HIF-1α-mediated glycolytic metabolism that would sustain CD8+ T cell activation.