Leucine metabolism as a novel approach to improve T cell performance in managing cancer

T cells can recognize and eliminate tumors in the same way as they recognize and destroy infectious agents. There are a number of mechanisms by which tumors may evade or silence the immune response. Depriving T cells of amino acids mitigates T cell function and allows tumors to evade the immune response. We studied the impact of the branched‐chain amino acid, leucine, and its degrading enzyme, the cytosolic branched‐chain aminotransferase (BCATc) on T cell activation as a novel approach to improve T cell performance in managing cancer. Our results showed that leucine was required for T cell activation and proliferation and its depletion promoted T cell tolerance. BCATc transcripts were up‐regulated in tolerant T cells that are unable to provide a productive immune response. We observed a 15‐ fold increase in BCATc protein levels, a 13‐fold increase in BCATc activity and 6‐fold increase in leucine transamination in tolerant T cells. Moreover, BCATc was up‐regulated in prostate cancer‐infiltrating regulatory T cells known to suppress the anti‐tumor immune response. Our results indicate that leucine is a critical factor for T cell activation while BCATc is a new candidate for an immunosuppressive enzyme that may represent a novel means by which tumors evade the immune response. In as much as inhibitors of BCATc are available, our study may provide novel targets for cancer vaccines. Research support, NIH/NIDDK (R01DK081563).