The emerging role of the branched chain aminotransferases, BCATc and BCATm, for anti-tumor T-cell immunity

Abstract

Challenges regarding successful immunotherapy are associated with the heterogeneity of tumors and the complex interactions within the surrounding tumor microenvironment (TME), particularly those between immune and tumor cells. Of interest, T cells receive a myriad of environmental signals to elicit differentiation to effector subtypes, which is accompanied by metabolic reprogramming needed to satisfy the high energy and biosynthetic demands of their activated state. However, T cells are subjected to immunosuppressive signals and areas of oxygen and nutrient depletion in the TME, which causes T-cell exhaustion and helps tumor cells escape immune detection. The cytosolic and mitochondrial branched chain amino transferases, BCATc and BCATm, respectively, are responsible for the first step of the branched chain amino acid (BCAA) degradation, of which, metabolites are shunted into various metabolic processes. In recent years, BCAT isoenzymes have been investigated for their role in a variety of cancers found throughout the body; however, a gap of knowledge exists regarding the role BCAT isoenzymes play within immune cells of the TME. The aim of this review is to summarize recent findings about BCAAs and their catabolism at the BCAT step during T-cell metabolic reprogramming and to discuss the BCAT putative role in the anti-tumor immunity of T cells. Not only does this review acknowledges gaps pertaining to BCAA metabolism in the TME but it also identifies the practical application of BCAA metabolism in T cells in response to cancer and spotlights a potential target for pharmacological intervention.

Crosstalk between arginine, glutamine, and the branched chain amino acid metabolism in the tumor microenvironment

“…BCAAs travel across the plasma membranes utilizing the heterodimeric transporter Slc7a5/Slc3a2. As stated earlier, this transporter works in antiport with Slc1a5 where glutamine efflux proceeds BCAA influx (6,58). Once inside the cells, BCAAs are incorporated into protein or subjected to degradation by the cytosolic branched chain aminotransferase, BCATc (6).…”

“…Arginine, glutamine, and the BCAAs are needed to support the increased biosynthetic and bioenergetic demands of the growing tumor and the incoming tumor infiltrating lymphocytes (TILs) (6)(7)(8). These amino acids interconnect at several metabolic steps.…”

Metabolic Heterogeneity, Plasticity, and Adaptation to “Glutamine Addiction” in Cancer Cells: The Role of Glutaminase and the GTωA [Glutamine Transaminase—ω-Amidase (Glutaminase II)] Pathway

“…Cancer cells exert significant control over the TME and thus can exhaust T-cell surveillance by limiting nutrient availability, releasing immunosuppressive cytokines, or creating a hypoxic environment. As noted, cancer cells and immune cells exhibit high demands for glutamine, arginine, and BCAAs to sustain growth and proper functioning [ 262 , 263 ]. Thus, inhibiting transport or utilization of these essential nutrients would be detrimental to metabolism of both cancer cells and cytotoxic T-cells.…”

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy

“…One member of the LAT family, LAT1, plays an especially important role in facilitating the increased uptake of BCAAs during T-cell activation ( 127 ). Two notable branched chain amino transferases, BCATc and BCATm, are responsible for catalyzing the first step in the degradation of the BCAAs isoleucine, leucine, and valine ( 128 ). Although several studies have shown that BCAT isoenzymes are highly expressed across different cancer types, the importance of these enzymes in mediating immunosuppressive effects is only recently garnering attention ( 128 – 130 ).…”

“…Two notable branched chain amino transferases, BCATc and BCATm, are responsible for catalyzing the first step in the degradation of the BCAAs isoleucine, leucine, and valine ( 128 ). Although several studies have shown that BCAT isoenzymes are highly expressed across different cancer types, the importance of these enzymes in mediating immunosuppressive effects is only recently garnering attention ( 128 – 130 ). One investigation reported that BCAT1 expression was positively correlated with immune checkpoint genes in several cancers ( 131 ).…”