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Hyperactivation of mTOR/eIF4E Signaling Pathway Promotes the Production of Tryptophan-To-Phenylalanine Substitutants

Zi-Qi Zheng1, Cheng-Rui Zhong2, Cheng-Zhi Wei1

  • 1Department of Gastric Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 12, 2024
PubMed

Insights

Chronic interferon-γ (IFN-γ) exposure in EBV-positive gastric cancer causes tryptophan depletion, leading to aberrant peptide production. Targeting the mTOR/eIF4E pathway may enhance immunotherapy for these patients.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Messenger RNA translation is regulated to maintain protein synthesis and cellular balance.
  • Chronic interferon-γ (IFN-γ) exposure in cancers can deplete tryptophan (Trp) via the indoleamine-2,3-dioxygenase (IDO)-kynurenine pathway.
  • This depletion can cause aberrant peptide production through ribosomal frameshifting and Trp codon reassignment (W>F substitutants).

Purpose of the Study:

  • To investigate the effect of tryptophan depletion on aberrant peptide generation via ribosomal mistranslation in gastric cancer (GC).
  • To explore the role of the mTOR/eIF4E signaling pathway in W>F substitutant production and antigen presentation in EBV-positive GC.
  • To assess the potential of targeting this pathway for anti-tumor immunotherapy.

Main Methods:

  • Analysis of infiltrating lymphocytes and IFN-γ secretion in EBV-positive GC.
  • Measurement of IDO1 expression and tryptophan levels.
  • Investigation of W>F substitutant production and antigen presentation.
  • Assessment of mTOR/eIF4E pathway activation and inhibition effects.

Main Results:

  • EBV-positive GC exhibits abundant infiltrating lymphocytes secreting IFN-γ, upregulating IDO1, and causing Trp shortage and W>F substitutants.
  • W>F substitutant production is linked to antigen presentation and mTOR/eIF4E pathway activation.
  • Inhibition of the mTOR/eIF4E pathway or EIF4E reduced W>F substitutant production and antigen presentation.

Conclusions:

  • The mTOR/eIF4E pathway accelerates aberrant peptide production and boosts immune activation via W>F substitutants in EBV-positive GC.
  • This pathway represents a vulnerability in gastric cancer.
  • EBV-positive GC patients with hyperactivated mTOR/eIF4E may benefit from anti-tumor immunotherapy.
Keywords:
EBV‐positive gastric canceraberrant mRNA translationcodon reassignmentsubstitutantstryptophan

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