The stress kinase GCN2 does not mediate suppression of antitumor T cell responses by tryptophan catabolism in experimental melanomas
2016
ABSTRACTTryptophan metabolism is a key process that shapes the immunosuppressive
tumor microenvironment. The two rate-limiting enzymes that mediate tryptophan depletion,
indoleamine-2,3-dioxygenase(IDO) and tryptophan-2,3-
dioxygenase(TDO), have moved into the focus of research and inhibitors targeting IDO and TDO have entered clinical trials. Local tryptophan depletion is generally viewed as the crucial immunosuppressive mechanism. In T cells, the kinase general control non-
derepressible2 (GCN2) has been identified as a
molecular sensorof tryptophan deprivation. GCN2 activation by tryptophan depletion induces apoptosis and mitigates T cell proliferation. Here, we investigated whether GCN2 attenuates tumor rejection in experimental B16 melanoma using T cell-specific Gcn2 knockout mice. Our data demonstrate that GCN2 in T cells did not affect immunity to B16 tumors even when animals were treated with antibodies targeting cytotoxic T lymphocyte antigen-4 (CTLA4). GCN2-deficient gp100 TCR-transgenic T
cel...
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