eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer

Shruthy Suresh, Bei Bei Chen, Jingfei Zhu, Ryan J. Golden, Changzheng Lu, Bret M. Evers, Nicole Novaresi, Bethany Smith, Xiaowei Zhan, Vanessa Schmid, Sojeong Jun, Chelsea M. Karacz, Michael Peyton, Lin Zhong, Zhuoyu Wen, Adwait Amod Sathe, Chao Xing, Carmen Behrens, Ignacio I. Wistuba, Guanghua XiaoYang Xie, Yang Xin Fu, John D. Minna, Joshua T Mendell, Kathryn A O'Donnell-Mendell

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)533-545
Number of pages13
JournalNature Cancer
Volume1
Issue number5
DOIs
StatePublished - May 1 2020

ASJC Scopus subject areas

  • Medicine(all)

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