Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses

Abstract

The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. "Lactagenic" or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege.

Keywords: cancer; cytokines; immune evasion; lactate; metabolism.

Figure 1

Scheme summarizing metabolic differences between normal and cancer cells and metabolic symbiosis. In normal cells, glucose (Glc) is initially metabolized to pyruvate and further to carbon dioxide (CO₂) through tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS) processes in the mitochondria, generating 36 ATP molecules per Glc molecule consumed (A). In this process, O₂ is indispensable, since it is used as the final electron acceptor (A). However, in cancer cells undergoing aerobic glycolysis (Warburg effect), Glc is broken down into pyruvate and finally converted into lactate, deviating Glc metabolites from energy production to anabolic process. This event generates two ATP molecules per Glc molecule. The panel (B) illustrates an event named metabolic symbiosis. It has been well documented that when cancer cells are near or distant of blood vessels, they are well or poorly oxygenated, respectively. It is also known that when cancer cells are subject to low oxygen tension (↓O₂) hypoxia-inducible factor-1α (HIF-1α) is stabilized, increasing the transcriptional activation of genes encoding glucose transporters (GLUTs), lactate dehydrogenase A (LDHA), as well as the uptake of Glc and secretion of lactate and protons out of cytoplasm through the monocarboxylated transporter 4 (MCT4). However, when transformed cells are close to blood vessels and the availability of O₂ is enough, lactate is taken by monocarboxylated transporter 1 (MCT1) and utilized as energy source after conversion into pyruvate by lactate dehydrogenase B (LDHB). In this way, lactate may not be pointed out as a waste metabolite, since it is reused by different cell subpopulations in a tumor.

Figure 2

Overview of immunosuppressive effects of lactate in the tumor microenvironment (TME). In a hypoxic environment, Glc enters the cell via glucose transporter (GLUT) 1 and is broken down into pyruvate and then in lactate, which is transported out of the cell via monocarboxylated transporter 4 (MCT4). The lactate produced by transformed cells culminates in an acidified TME. This phenomenon is able to suppress the anticancer immune responses, particularly through impaired T and natural killer (NK) cells activation, reduced antigen presentation, compromised dendritic cell (DC) differentiation and maturation. It also promotes the emergence of the M2 Mϕ, which secretes high levels of pro-carcinogenic cytokines, such as transforming growth factor-beta (TGF-β) and vascular endothelial growth factor (VEGF), involved in processes such as epithelial–mesenchymal transition (EMT) and angiogenesis, events implicated in metastasis and cancer progression.