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. Cancer Res; 76(21); 6193-204. ©2016 AACR.
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Elina
authors.initials: E
authors.lastname: Timosenko
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Hemza
authors.initials: H
authors.lastname: Ghadbane
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Silk
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Dawn
authors.initials: D
authors.lastname: Shepherd
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Uzi
authors.initials: U
authors.lastname: Gileadi
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Howson
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Laynes
authors.affiliation: Ludwig Cancer Research, New York, New York.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: Ludwig Cancer Research, New York, New York.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Strausberg
authors.affiliation: Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark, Lyngby, Denmark.
authors.forename: Lars R
authors.initials: LR
authors.lastname: Olsen
authors.affiliation: The Computational Biology Research Group (CBRG), Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Stephen
authors.initials: S
authors.lastname: Taylor
authors.affiliation: Department of Oncology, Old Road Campus Research Building, University of Oxford, Oxford, United Kingdom.
authors.forename: Francesca M
authors.initials: FM
authors.lastname: Buffa
authors.affiliation: Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.
authors.forename: Richard
authors.initials: R
authors.lastname: Boyd
authors.affiliation: MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom. vincenzo.cerundolo@imm.ox.ac.uk.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Cerundolo
mesh_terms: D051701:Activating Transcription Factor 4 / Q000502:physiology*; D026962:Amino Acid Transport System ASC / Q000502:physiology*; D026905:Amino Acid Transport Systems / Q000235:genetics*; D045744:Cell Line, Tumor; D065150:Cellular Reprogramming; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000502:physiology*; D015778:Minor Histocompatibility Antigens / Q000502:physiology*; D009369:Neoplasms / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D026962:Amino Acid Transport System ASC; D026905:Amino Acid Transport Systems; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D015778:Minor Histocompatibility Antigens; C420506:SLC1A5 protein, human; D051701:Activating Transcription Factor 4; D014364:Tryptophan