eIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer
| Autor: | Ryan J. Golden, Yang Xin Fu, Xiaowei Zhan, Bret M. Evers, Sojeong Jun, Carmen Behrens, Jingfei Zhu, Guanghua Xiao, Michael Peyton, Joshua T. Mendell, Vanessa Schmid, Chelsea M. Karacz, Adwait Amod Sathe, Kathryn A. O'Donnell, Chao Xing, Nicole Novaresi, Lin Zhong, Bethany Smith, Shruthy Suresh, Ignacio I. Wistuba, Zhuoyu Wen, John D. Minna, Yang Xie, Changzheng Lu, Beibei Chen |
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| Rok vydání: | 2020 |
| Předmět: |
Cancer Research
Lung Neoplasms T cell medicine.medical_treatment Heme Article B7-H1 Antigen 03 medical and health sciences 0302 clinical medicine PD-L1 medicine Humans Integrated stress response Eukaryotic Initiation Factors Lung cancer biology business.industry Translation (biology) Immunotherapy medicine.disease Immune checkpoint medicine.anatomical_structure Oncology 030220 oncology & carcinogenesis Cancer cell biology.protein Cancer research business |
| Zdroj: | Nat Cancer |
| ISSN: | 2662-1347 |
| Popis: | Cancer cells express high levels of programmed death ligand 1 (PD-L1), a ligand of the programmed cell death protein 1 (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 a first-line therapy for patients with lung cancer. 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, allowing bypass of inhibitory upstream open reading frames in the PD-L1 5′ untranslated region, resulting in enhanced PD-L1 translation and suppression of anti-tumor immunity. We demonstrate that integrated stress-response-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. O’Donnell and colleagues report that activation of the integrated stress response in non-small cell lung cancer cells by impairing heme production leads to enhanced PD-L1 translation in an eIF5B-dependent manner. |
| Databáze: | OpenAIRE |
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