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

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.