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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. Cancer Res; 76(21); 6193-204. ©2016 AACR.

Original publication

DOI

10.1158/0008-5472.CAN-15-3502

Type

Journal article

Journal

Cancer Res

Publication Date

01/11/2016

Volume

76

Pages

6193 - 6204

Keywords

Activating Transcription Factor 4, Amino Acid Transport System ASC, Amino Acid Transport Systems, Cell Line, Tumor, Cellular Reprogramming, Humans, Indoleamine-Pyrrole 2,3,-Dioxygenase, Minor Histocompatibility Antigens, Neoplasms, Tryptophan