| Summary: | <p>A large proportion of human tumours exploit tryptophan catabolism as a means to suppress T cell activity in the tumour microenvironment. However, the mechanisms that allow tumour cells to resist the detrimental effects of local tryptophan depletion have so far remained obscure. Here we demonstrate that shortage of tryptophan induced by the expression of tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) results in ATF4-dependent reprogramming of the amino acid transporter expression profile in tumour cells. Specifically, we show that tumour cells undergoing tryptophan starvation enhance the expression of several amino acid transporters including SLC1A5 and its truncated isoforms through activation of the ATF4 stress response pathway. While upregulation of SLC1A5 leads to improved glutamine and tryptophan uptake, the knockdown of this amino acid transporter inhibits tumour cell proliferation under low tryptophan conditions. In contrast to tumour cells, T cells fail to upregulate SLC1A5 during tryptophan starvation, but can enhance its expression upon cognate antigen T cell receptor engagement. SLC1A5 expression is also enriched in T regulatory cells and IDO-expressing dendritic cells, as well as in tumours growing under conditions of IDO-mediated tryptophan degradation in vivo. Finally, SLC1A5 expression correlates with IDO expression in several human tumours in silico, which is associated with poor prognosis in brain lower grade glioma. In conclusion, our results highlight key differences in the ability of tumour cells and T cells to adapt to tryptophan starvation and shed light on the previously unappreciated role of amino acid transport in IDO- and TDO-mediated immune escape.</p>
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