The Tumor Microenvironment-A Metabolic Obstacle to NK Cells' Activity

Abstract

NK cells have unique capabilities of recognition and destruction of tumor cells, without the requirement for prior immunization of the host. Maintaining tolerance to healthy cells makes them an attractive therapeutic tool for almost all types of cancer. Unfortunately, metabolic changes associated with malignant transformation and tumor progression lead to immunosuppression within the tumor microenvironment, which in turn limits the efficacy of various immunotherapies. In this review, we provide a brief description of the metabolic changes characteristic for the tumor microenvironment. Both tumor and tumor-associated cells produce and secrete factors that directly or indirectly prevent NK cell cytotoxicity. Here, we depict the molecular mechanisms responsible for the inhibition of immune effector cells by metabolic factors. Finally, we summarize the strategies to enhance NK cell function for the treatment of tumors.

Keywords: NK cell; metabolism; tumor microenvironment.

Figure 1

Overview of the NK cell receptors and their respective ligands. NK cells’ cytotoxicity is tightly regulated through the complex balance between inhibitory and activating signals originating from different NK cell receptors.

Figure 2

A schematic characteristic of the tumor microenvironment metabolites and other factors impacting NK cell effector function. Within the tumor microenvironment cancer cells consume large amounts of glucose and produce lactate and subsequent extracellular acidosis. Glycolytic conversion of glucose into pyruvate also stimulates the production of ROS. Tumor cells, as well as stromal cells, compete for nutrients such as glucose, glutamine, and amino acids. Thus, cancer cells together with stroma cells increase amino acids consumption and upregulate key amino acid metabolism enzymes, such as IDO and Arg1/2, leading to the accumulation of amino acids’ immunosuppressive metabolites, such as kynurenine. Tumor cells also generate extracellular adenosine through the ectonucleotidases CD39 and CD73. Moreover, high oxygen consumption by tumor cells can cause hypoxic conditions, which sustains HIF-1α, which in turn promotes glycolytic metabolism by upregulation of GLUT1 and lactate production by modulation of lactate transporters expression. Moreover, tumor and tumor-associated cells secrete factors, which prevent NK cell activation, such as TGF-β, IL-6, IL-10, and PGE₂.

Figure 3

NK cell metabolism. (A) Key regulators of NK cells metabolism. Activated NK cells are characterized by increased glucose uptake and OXPHOS. mTORC1 is the key factor, controlling NK cell metabolism by upregulation of NK cells’ glycolysis and OXPHOS. mTORC1 is also involved in activation of cMYC and SREBP, which may further modulate glycolysis and OXPHOS. (B) Mechanisms disrupting NK cell metabolism in cancer. Many factors within the tumor microenvironment, can directly impact rates of glycolysis and OXPHOS by interfering with mTORC1, cMYC, or FBP1 activity. Moreover, mitochondrial dysfunction through ROS accumulation can be induced by intracellular lactate accumulation.

Figure 4

Tumor microenvironment shapes NK cells’ migration to the tumor site by upregulation of CXCR4 receptor through HIF-1α and TGF-β. It also downregulates CX3CR1 expression by TGF-β and CCR7 levels by PGE₂, thus limiting their recruitment to the tumor sites. The formation of NK-cell lytic synapse can be divided into recognition, effector and termination stages. Within the tumor microenvironment factors such as PGE₂, tryptophan metabolites, TGF-β, ADO, ROS, and lactate can downregulate NK cells activating receptors, including NKp46, NKp44, NKp30, and CD16 and inhibitory receptors, such as KIR2DL1 and KIR2DL3. On the other hand, during the effector stage, the same metabolites can decrease expression of the lytic granule molecules, such as perforin and granzymes. Also, they can influence NK cells’ ability for cytokine production, including IFN-γ and TNF-α.