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.

Monocarboxylate transporter 1 blockade with AZD3965 inhibits lipid biosynthesis and increases tumour immune cell infiltration

“…Tumour microenvironment conditioning through reduced lactate export is likely to be the main mechanism for the increased tumour immune cell infiltration given the known inhibitory effects of lactate on anti-tumour immune cell activity and expansion, and the lack of effect on spleen immune cell phenotype. [34][35][36] Interestingly, our human PBMC data also show that AZD3965 inhibits MCT1 in immune cells themselves potentially modulating their metabolism and also their activity. 37 In agreement with this observation, previous work has shown that MCT1 inhibition has an immunosuppressive effect on T cells, preventing their expansion upon activation.…”

Lactate secreted by cervical cancer cells modulates macrophage phenotype

“…Cervical cancer is caused by persistent infection with high oncogenic risk HPV types and has been shown to express MCTs,20 indicating lactate secretion. Many solid tumors display glycolytic metabolism and secrete lactate, leading to suppression of antitumor responses 44. Our results show that cervical cancer cell lines secrete lactate and that this molecule can be detected in the plasma of patients with cervical lesions and cervical cancer.…”

“…Cervical cancer is caused by persistent infection with high oncogenic risk HPV types and has been shown to express MCTs, indicating lactate secretion. Many solid tumors display glycolytic metabolism and secrete lactate, leading to suppression of antitumor responses …”

Loss of Rb1 Enhances Glycolytic Metabolism in Kras-Driven Lung Tumors In Vivo

“…Beyond the effects on cell proliferation, tumor cell-derived lactate produced during aerobic glycolysis has a profound effect on the tumor microenvironment and cancer progression [34]. Extracellular lactate has deleterious effects on infiltrating T-cells, while serving as a nutrient source for immunosuppressive tumor-associated macrophages [34][35][36]. pRb-deficient tumors exhibited increased lactate production from glucose ( Figure 3F), yet whether this influences the immune response in the TME remains unclear.…”