| First Author | Suresh S | Year | 2020 |
| Journal | Nat Cancer | Volume | 1 |
| Issue | 5 | Pages | 533-545 |
| PubMed ID | 32984844 | Mgi Jnum | J:304432 |
| Mgi Id | MGI:6508488 | Doi | 10.1038/s43018-020-0056-0 |
| Citation | Suresh S, et al. (2020) eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer. Nat Cancer 1(5):533-545 |
| abstractText | 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. Clinical trials utilizing antibodies that disrupt the PD-1/PD-L1 checkpoint have yielded remarkable results, with anti-PD-1 immunotherapy approved as first-line therapy for lung cancer patients. We used CRISPR-based screening to identify regulators of PD-L1 in human lung cancer cells, revealing potent induction of PD-L1 upon disruption of heme biosynthesis. 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 demonstrated that ISR-dependent PD-L1 translation requires the translation initiation factor eIF5B. eIF5B overexpression, which is frequent in lung adenocarcinomas and associated with poor prognosis, is sufficient to induce PD-L1. These findings illuminate mechanisms of immune checkpoint activation and identify targets for therapeutic intervention. |
