Targeting L-Lactate Metabolism to Overcome Resistance to Immune Therapy of Melanoma and Other Tumor Entities.

René G Feichtinger,Roland Lang

doi:10.1155/2019/2084195

Abstract

Although immunotherapy plays a significant role in tumor therapy, its efficacy is impaired by an immunosuppressive tumor microenvironment. A molecule that contributes to the protumor microenvironment is the metabolic product lactate. Lactate is produced in large amounts by cancer cells in response to either hypoxia or pseudohypoxia, and its presence in excess alters the normal functioning of immune cells. A key enzyme involved in lactate metabolism is lactate dehydrogenase (LDH). Elevated baseline LDH serum levels are associated with poor outcomes of current anticancer (immune) therapies, especially in patients with melanoma. Therefore, targeting LDH and other molecules involved in lactate metabolism might improve the efficacy of immune therapies. This review summarizes current knowledge about lactate metabolism and its role in the tumor microenvironment. Based on that information, we develop a rationale for deploying drugs that target lactate metabolism in combination with immune checkpoint inhibitors to overcome lactate-mediated immune escape of tumor cells.

Highlights

Long regarded as merely a metabolic waste product, there is growing evidence that L-lactate produced in excess by cancer cells favors tumor growth and metastasis
Glucose serves as a carbon source for anabolic processes. e excess carbon is diverted into branching pathways emanating from glycolysis and is used for the generation of building blocks such as nucleotides, lipids, and proteins [7, 16, 19, 20]. Another theory proposes that tumors shut down oxidative phosphorylation (OXPHOS) to reduce the damage caused by reactive oxygen species (ROS) while maintaining a level necessary for signaling, e.g., especially important for chromatin metabolism [20]
lactate dehydrogenase (LDH) in the mitochondrial intermembrane space (IMS) generates NADH used by malate dehydrogenase, which converts oxaloacetate to malate. e malate-α-ketoglutarate (α-KG) antiporter (SLC25A11) transports malate into the mitochondrial matrix in exchange for α-KG that is transported to the IMS, where it is metabolized to glutamate by the enzyme aspartate aminotransferase (AAT)

Summary

Introduction

Long regarded as merely a metabolic waste product, there is growing evidence that L-lactate produced in excess by cancer cells favors tumor growth and metastasis. Us, in principle, targeting lactate metabolism could be a strategy to bolster the effectiveness of cancer therapies and improve patient outcomes Before delving into these therapeutic possibilities, we begin with an overview of lactate metabolism, especially as it relates to energy production in cancer cells. Pyruvate oxidation is downregulated and replaced by lactate production, catalyzed by LDH, without ATP generation. E excess carbon is diverted into branching pathways emanating from glycolysis and is used for the generation of building blocks such as nucleotides, lipids, and proteins [7, 16, 19, 20] Another theory proposes that tumors shut down OXPHOS to reduce the damage caused by reactive oxygen species (ROS) while maintaining a level necessary for signaling, e.g., especially important for chromatin metabolism [20]

Other Models

Role of Hypoxia

L-Lactate as a Biomarker in Melanoma and Other Neoplasms

Findings

Lactate and the Tumor Microenvironment