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The Integrated Stress Response Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung

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

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

Cancer Research
|May 6, 2025
PubMed

Insights

The integrated stress response (ISR) pathway helps cancer cells survive by increasing immune checkpoints like PD-L1 and CD155. Inhibiting ISR may offer a new lung cancer treatment strategy.

Area of Science:

  • Immunology
  • Cancer Biology
  • Molecular Biology

Background:

  • The integrated stress response (ISR) is crucial for cancer cell survival in the tumor microenvironment.
  • ISR activation promotes tumor immune evasion by inducing Programmed Death-Ligand 1 (PD-L1).

Purpose of the Study:

  • To identify additional immune checkpoint proteins regulated by the ISR.
  • To elucidate ISR-mediated mechanisms of tumor immune escape.

Main Methods:

  • Investigated ISR-coordinated regulation of immune checkpoints.
  • Analyzed translation enhancement of PD-L1 and CD155 via 5' UTRs.
  • Correlated PD-L1 and CD155 expression in human lung tumors.

Main Results:

  • ISR coordinately induced both CD155 and PD-L1 expression.
  • Enhanced translation of CD155 and PD-L1 by bypassing upstream open reading frames.
  • Found a significant correlation between PD-L1 and CD155 in primary lung tumors.
  • ISR activation accelerated tumor growth and impaired T cell function.

Conclusions:

  • The ISR coordinates the expression of multiple immune checkpoints, including PD-L1 and CD155.
  • Combined blockade of PD-1, TIGIT, and ISR inhibition (ISRIB) can overcome ISR-driven tumor immune escape.
  • This study suggests a novel therapeutic strategy for lung cancer targeting the ISR.

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