Nutritional stress induced by tryptophan-degrading enzymes results in ATF4-dependent reprogramming of the amino acid transporter profile in tumor cells

Elina Timosenko, Hemza Ghadbane, Jonathan D. Silk, Dawn Shepherd, Uzi Gileadi, Lauren J. Howson, Robert Laynes, Qi Zhao, Robert L. Strausberg, Lars R. Olsen, Stephen Taylor, Francesca M. Buffa, Richard Boyd, Vincenzo Cerundolo

Research output: Contribution to journalArticleResearchpeer-review

21 Citations (Scopus)


Tryptophan degradation is an immune escape strategy shared by many tumors. However, cancer cells' compensatory mechanisms remain unclear. We demonstrate here that a shortage of tryptophan caused by expression of indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) resulted in ATF4-dependent upregulation of several amino acid transporters, including SLC1A5 and its truncated isoforms, which in turn enhanced tryptophan and glutamine uptake. Importantly, SLC1A5 failed to be upregulated in resting human T cells kept under low tryptophan conditions but was enhanced upon cognate antigen T-cell receptor engagement. Our results highlight key differences in the ability of tumor and T cells to adapt to tryptophan starvation and provide important insights into the poor prognosis of tumors coexpressing IDO and SLC1A5.

Original languageEnglish
Pages (from-to)6193-6204
Number of pages12
JournalCancer Research
Issue number21
Publication statusPublished - 1 Nov 2016
Externally publishedYes

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