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 Rønn Olsen; Stephen Taylor; Francesca M. Buffa; Richard Boyd; Vincenzo Cerundolo

doi:10.1158/0008-5472.CAN-15-3502

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 Rønn Olsen, Stephen Taylor, Francesca M. Buffa, Richard Boyd, Vincenzo Cerundolo

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Abstract

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 language	English
Journal	Cancer Research
Volume	76
Issue number	21
Pages (from-to)	6193-6204
Number of pages	12
ISSN	0008-5472
DOIs	https://doi.org/10.1158/0008-5472.CAN-15-3502
Publication status	Published - 2016

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Timosenko, E., Ghadbane, H., Silk, J. D., Shepherd, D., Gileadi, U., Howson, L. J., Laynes, R., Zhao, Q., Strausberg, R. L., Olsen, L. R., Taylor, S., Buffa, F. M., Boyd, R., & Cerundolo, V. (2016). Nutritional Stress Induced by Tryptophan-Degrading Enzymes Results in ATF4-Dependent Reprogramming of the Amino Acid Transporter Profile in Tumor Cells. Cancer Research, 76(21), 6193-6204. https://doi.org/10.1158/0008-5472.CAN-15-3502

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title = "Nutritional Stress Induced by Tryptophan-Degrading Enzymes Results in ATF4-Dependent Reprogramming of the Amino Acid Transporter Profile in Tumor Cells",

abstract = "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.",

author = "Elina Timosenko and Hemza Ghadbane and Silk, {Jonathan D} and Dawn Shepherd and Uzi Gileadi and Howson, {Lauren J.} and Robert Laynes and Qi Zhao and Strausberg, {Robert L.} and Olsen, {Lars R{\o}nn} and Stephen Taylor and Buffa, {Francesca M.} and Richard Boyd and Vincenzo Cerundolo",

year = "2016",

doi = "10.1158/0008-5472.CAN-15-3502",

language = "English",

volume = "76",

pages = "6193--6204",

journal = "Cancer research. Supplement",

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publisher = "American Association for Cancer Research (A A C R)",

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Timosenko, E, Ghadbane, H, Silk, JD, Shepherd, D, Gileadi, U, Howson, LJ, Laynes, R, Zhao, Q, Strausberg, RL, Olsen, LR, Taylor, S, Buffa, FM, Boyd, R & Cerundolo, V 2016, 'Nutritional Stress Induced by Tryptophan-Degrading Enzymes Results in ATF4-Dependent Reprogramming of the Amino Acid Transporter Profile in Tumor Cells', Cancer Research, vol. 76, no. 21, pp. 6193-6204. https://doi.org/10.1158/0008-5472.CAN-15-3502

TY - JOUR

T1 - Nutritional Stress Induced by Tryptophan-Degrading Enzymes Results in ATF4-Dependent Reprogramming of the Amino Acid Transporter Profile in Tumor Cells

AU - Timosenko, Elina

AU - Ghadbane, Hemza

AU - Silk, Jonathan D

AU - Shepherd, Dawn

AU - Gileadi, Uzi

AU - Howson, Lauren J.

AU - Laynes, Robert

AU - Zhao, Qi

AU - Strausberg, Robert L.

AU - Olsen, Lars Rønn

AU - Taylor, Stephen

AU - Buffa, Francesca M.

AU - Boyd, Richard

AU - Cerundolo, Vincenzo

PY - 2016

Y1 - 2016

N2 - 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.

AB - 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.

U2 - 10.1158/0008-5472.CAN-15-3502

DO - 10.1158/0008-5472.CAN-15-3502

M3 - Journal article

C2 - 27651314

SN - 0576-6656

VL - 76

SP - 6193

EP - 6204

JO - Cancer research. Supplement

JF - Cancer research. Supplement

IS - 21

ER -

Nutritional Stress Induced by Tryptophan-Degrading Enzymes Results in ATF4-Dependent Reprogramming of the Amino Acid Transporter Profile in Tumor Cells

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