GSE129968
EIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer
Cancer cells express high levels of PD-L1, a ligand of the PD-1 receptor on T  cells, allowing tumors to suppress T cell activity 1-3. Clinical trials utilizing  monoclonal antibodies that disrupt the PD-1/PD-L1 immune checkpoint have  yielded remarkable results, with PD-1 immunotherapy approved as a first-line  therapy for human lung cancer patients 4-6. Despite significant progress in  targeting this pathway, the mechanisms through which PD-L1 is upregulated in  non-small cell lung cancer (NSCLC) and other tumor types remain incompletely  understood. Here we used CRISPR-based screening to identify regulators of PDL1  in human lung cancer cells, revealing potent induction of PD-L1 levels upon  disruption of the heme biosynthesis pathway. Impairment of heme production  activates the integrated stress response (ISR), allowing bypass of inhibitory  upstream open reading frames in the PD-L1 5¢ UTR, resulting in enhanced PD-L1  translation and suppression of anti-tumor immunity. We further demonstrated  that ISR-dependent translation of PD-L1 requires the translation initiation factor  EIF5B. EIF5B overexpression, which is frequent in human lung cancers and is  associated with poor prognosis, is sufficient to induce PD-L1. These findings  uncover a new mechanism of immune checkpoint activation and suggest novel  targets for therapeutic intervention. Overall design: H358 cells were transuced with lentiCRISPR V2 library virus, selected and sorted by PD-L1-APC. Genomic DNA was isolated and deep sequencing was performed to identify sgRNA enriched in sorted vs unsorted cells