ISR Pathway Inhibition as a Universal Sensitizer for Checkpoint Blockade Across Cancer Types

Thomas-Jardin et al. (2024, Cancer Research) revealed that ISR activation upregulates multiple immune checkpoints (PD-L1, CD155) in lung cancer, promoting immune evasion. The novelty here is to systematically test ISR inhibition alongside checkpoint blockade in a range of cancer models (breast, colorectal, prostate, etc.), hypothesizing that ISR is a conserved resistance mechanism. The project would use both in vitro and in vivo models, including single-cell RNA-seq to map immune cell shifts. This idea departs from current literature by treating ISR not just as a lung cancer phenomenon but as a pan-cancer target for overcoming checkpoint inhibitor resistance.

References:

1. Abstract 7528: Coordinated regulation of critical immune checkpoint proteins by the integrated stress response (ISR) pathway in lung cancer. Shayna Thomas-Jardin, Shruthy Suresh, C. Lewis, Chul Ahn, Bret M Evers, J. Minna, Kathryn A. O’Donnell (2024). Cancer Research.