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Coordinated translational control of multiple immune checkpoints by the integrated stress response pathway in lung

Shayna Thomas-Jardin1, Shruthy Suresh1,2,3, Ariana Arce1

  • 1Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX, USA.

Biorxiv : the Preprint Server for Biology
|November 18, 2024
PubMed

Insights

The integrated stress response (ISR) pathway promotes cancer immune evasion by upregulating PD-L1 and CD155. Inhibiting the ISR enhances anti-cancer immunity, offering a new therapeutic strategy for lung cancer.

Area of Science:

  • Cancer immunology
  • Molecular biology
  • Tumor microenvironment

Background:

  • The integrated stress response (ISR) is crucial for cancer cell survival under stress.
  • ISR activation leads to Programmed Death Ligand 1 (PD-L1) induction, suppressing anti-tumor immunity.
  • Tumor immune escape mechanisms involve multiple immune checkpoint proteins.

Purpose of the Study:

  • To identify additional immune checkpoint proteins regulated by the ISR.
  • To elucidate the mechanisms of ISR-mediated tumor immune escape.
  • To explore novel therapeutic strategies for lung cancer.

Main Methods:

  • Analysis of ISR-regulated gene expression and protein translation.
  • Investigating the role of upstream open reading frames (uORFs) in 5' UTRs.
  • Correlative analysis of PD-L1 and CD155 expression in primary human lung tumors.
  • Evaluating the efficacy of combined PD-1 blockade and ISR inhibition (ISRIB) in preclinical models.

Main Results:

  • The ISR coordinately induces both PD-L1 and CD155 expression.
  • ISR activation enhances the translation of PD-L1 and CD155 by bypassing inhibitory uORFs.
  • A significant correlation between PD-L1 and CD155 expression was observed in human lung tumors.
  • ISR activation accelerates tumorigenesis and impairs T cell function.
  • Combined PD-1 blockade and ISR inhibition overcome these effects.

Conclusions:

  • The ISR represents a novel regulatory mechanism for coordinated immune checkpoint protein expression.
  • The ISR pathway is a therapeutic vulnerability in lung cancer.
  • Combining PD-1 blockade with ISR inhibition presents a promising new therapeutic strategy for lung cancer patients.

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