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Radiosynthesis of 1-2-[18F]Fluoroethyl-L-Tryptophan using a One-pot, Two-step Protocol
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Radiosynthesis of 1-2-[18F]Fluoroethyl-L-Tryptophan using a One-pot, Two-step Protocol

Published on: September 21, 2021

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

Elina Timosenko1, Hemza Ghadbane1, Jonathan D Silk1

  • 1MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.

Cancer Research
|September 22, 2016
PubMed

Insights

Tumors use tryptophan degradation to evade immune responses. Cancer cells compensate by upregulating amino acid transporters, unlike T cells, indicating a poor prognosis for tumors expressing indoleamine 2,3-dioxygenase (IDO) and SLC1A5.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • Tryptophan degradation is a known tumor immune escape mechanism.
  • The compensatory mechanisms of cancer cells facing tryptophan starvation are not fully understood.

Purpose of the Study:

  • To investigate the adaptive responses of cancer cells and T cells to tryptophan deficiency.
  • To elucidate the role of amino acid transporters in tumor immune evasion.

Main Methods:

  • Analysis of tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO).
  • Assessment of ATF4-dependent upregulation of amino acid transporters, including SLC1A5 and its isoforms.
  • Comparison of SLC1A5 regulation in tumor cells versus human T cells under varying tryptophan conditions.

Main Results:

  • IDO and TDO expression led to ATF4-dependent upregulation of SLC1A5 and its isoforms, enhancing tryptophan and glutamine uptake in cancer cells.
  • SLC1A5 upregulation was not observed in resting human T cells under low tryptophan conditions.
  • T-cell receptor engagement enhanced SLC1A5 in T cells, suggesting differential regulation.

Conclusions:

  • Tumor cells exhibit distinct adaptive mechanisms to tryptophan starvation compared to T cells.
  • The coexpression of IDO and SLC1A5 in tumors is associated with a poor prognosis.
  • Understanding these differences provides insights into cancer immune evasion strategies.

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