Branched‐chain ketoacids secreted by glioblastoma cells via MCT 1 modulate macrophage phenotype

Abstract

Elevated amino acid catabolism is common to many cancers. Here, we show that glioblastoma are excreting large amounts of branched-chain ketoacids (BCKAs), metabolites of branched-chain amino acid (BCAA) catabolism. We show that efflux of BCKAs, as well as pyruvate, is mediated by the monocarboxylate transporter 1 (MCT1) in glioblastoma. MCT1 locates in close proximity to BCKA-generating branched-chain amino acid transaminase 1, suggesting possible functional interaction of the proteins. Using models, we demonstrate that tumor-excreted BCKAs can be taken up and re-aminated to BCAAs by tumor-associated macrophages. Furthermore, exposure to BCKAs reduced the phagocytic activity of macrophages. This study provides further evidence for the eminent role of BCAA catabolism in glioblastoma by demonstrating that tumor-excreted BCKAs might have a direct role in tumor immune suppression. Our data further suggest that the anti-proliferative effects of MCT1 knockdown observed by others might be related to the blocked excretion of BCKAs.

Metabolic Modulation in Macrophage Effector Function

“…mTOR plays a key role in macrophages, providing a link between amino-acid availability, coupling this to growth, proliferation, and protein synthesis. Branched-chain ketoacids (BCKAs), a product of BCAA catabolism, has been shown to directly regulate macrophage function by reducing the phagocytic ability of TAMs ( 140 ). Further evidence for a role for BCAA comes from data demonstrating that BCAT1, the enzyme responsible for the first step in BCAA catabolism, regulates the metabolic reprogramming in human macrophages.…”

Biochemistry of proinflammatory macrophage activation

“…Administration of the selective BCAT1 inhibitor ERG240 (a leucine analogue) to mice resulted in reduced severity of immune-mediated inflammation in vivo, indicating that BCAT1 inhibition could also be of potential therapeutic interest [ 118 ]. A second study on the role of BCAT1 in macrophages found that glioblastoma cells secrete BCKAs via the monocarboxylate carrier 1 (MCT1) and that these BCKAs are taken up by tumor-associated macrophages [ 119 ]. BCKA uptake is potentially mediated by the MCT1 and/or MCT4 carriers, both of which are expressed in macrophages.…”

Glioblastoma Immune Landscape and the Potential of New Immunotherapies

“…Through the overexpression of branched chain amino acid transaminase 1 (BCAT1), glioma tumors excrete elevated levels of branched-chain ketoacids (BCKA) through MCT1. Which influx into TAMs and blunt their phagocytic activity ( 61 ). GBM TAMs were also shown to drive T cell dysfunction through elevated expression of the ectonucleosidase CD39 that, together with CD73, induces the production of the immunosuppressive metabolite adenosine ( 48 ).…”