Open AccesseIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer
Author(s) -
Shruthy Suresh,
Beibei Chen,
Jingfei Zhu,
Ryan Golden,
Changzheng Lu,
B. Mark Evers,
Nicole Novaresi,
Bethany Smith,
Xiaowei Zhan,
Vanessa Schmid,
Sojeong Jun,
Chelsea M. Karacz,
Michael Peyton,
Lin Zhang,
Zhe Wen,
Adwait Amod Sathe,
Chao Xing,
Carmen Behrens,
Ignacio I. Wistuba,
Guanghua Xiao,
Yang Xie,
Yang–Xin Fu,
John D. Minna,
Joshua T. Mendell,
Kathryn A. O’Donnell
Publication year - 2020
Publication title -
nature cancer
Language(s) - English
Resource type - Journals
ISSN - 2662-1347
DOI - 10.1038/s43018-020-0056-0
Subject(s) - integrated stress response , cancer research , lung cancer , immune checkpoint , eukaryotic translation , eukaryotic initiation factor , immunotherapy , translational regulation , translation (biology) , immune system , microbiology and biotechnology , biology , medicine , chemistry , immunology , messenger rna , biochemistry , gene
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.