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

Authors

Shayna Thomas-Jardin
Shruthy Suresh
Ariana Arce
Nicole Novaresi
Qing Deng
Emily Stein
Lisa Thomas
Cheryl Lewis
Chul Ahn
Bret M Evers
Esra A Akbay
Maria E Salvatierra
Wei Lu
Khaja Khan
Luisa M Solis Soto
Ignacio I Wistuba
John D Minna
Kathryn A O'Donnell

Publication Date

7-15-2025

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-24-3844

PMID

40327600

PMCID

PMC12260515

PubMedCentral® Posted Date

5-6-2025

PubMedCentral® Full Text Version

Post-print

Abstract

The integrated stress response (ISR) is an adaptive pathway hijacked by cancer cells to survive cellular stresses in the tumor microenvironment. ISR activation potently induces PD-L1, leading to suppression of antitumor immunity. In this study, we sought to uncover additional immune checkpoint proteins regulated by the ISR to elucidate mechanisms of tumor immune escape. The ISR coordinately induced cluster of differentiation 155 (CD155) and PD-L1, enhancing translation of both immune checkpoint proteins through bypass of inhibitory upstream open reading frames in their 5' untranslated regions. Analysis of primary human lung tumors identified a significant correlation between expression of PD-L1 and CD155. ISR activation accelerated tumorigenesis and inhibited T-cell function, which could be overcome by combining PD-1 and TIGIT blockade with the ISR inhibitor ISRIB. This study uncovers a mechanism by which two immune checkpoint proteins are coordinately regulated and suggests a therapeutic strategy for patients with lung cancer.

SIGNIFICANCE: The integrated stress response represents a targetable axis to improve the efficacy of immunotherapy in lung cancer by inhibiting the coordinated translational regulation of the PD-L1/PD-1 and CD155/TIGIT immune checkpoint pathways.

Keywords

Lung Neoplasms, Humans, B7-H1 Antigen, Mice, Animals, Tumor Microenvironment, Gene Expression Regulation, Neoplastic, Programmed Cell Death 1 Receptor, Cell Line, Tumor, Stress, Physiological, Protein Biosynthesis, Immune Checkpoint Proteins, Tumor Escape

Published Open-Access

yes

Recommended Citation

Thomas-Jardin, Shayna; Suresh, Shruthy; Arce, Ariana; et al., "The Integrated Stress Response Pathway Coordinates Translational Control of Multiple Immune Checkpoints in Lung Cancer" (2025). Faculty, Staff and Student Publications. 5145.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5145