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EIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer.

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.

SUBMITTER: Suresh S

PROVIDER: S-EPMC7511089 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Suresh Shruthy S Chen BeiBei B Zhu Jingfei J Golden Ryan J RJ Lu Changzheng C Evers Bret M BM Novaresi Nicole N Smith Bethany B Zhan Xiaowei X Schmid Vanessa V Jun Sojeong S Karacz Chelsea M CM Peyton Michael M Zhong Lin L Wen Zhuoyu Z Sathe Adwait Amod AA Xing Chao C Behrens Carmen C Wistuba Ignacio I II Xiao Guanghua G Xie Yang Y Fu Yang-Xin YX Minna John D JD Mendell Joshua T JT O'Donnell Kathryn A KA

Nature cancer 20200420 5

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 ...[more]

PMID: 32984844

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Project description:BackgroundEukaryotic translation initiation factors (eIFs) are the key factors to synthesize translation initiation complexes during the synthesis of eukaryotic proteins. Besides, eIFs are especially important in regulating the immune function of tumor cells. However, the effect mechanism of eIFs in prostate cancer remains to be studied, which is precisely the purpose of this study.MethodsIn this study, three groups of prostate cancer cells were investigated. One group had its eIF5B gene knocked down; another group had its Programmed death 1 (PD-L1) overexpressed; the final group had its Wild-type p53-induced gene 1 (Wig1) overexpressed. Genetic alterations of the cancer cells were performed by plasmid transfection. The expression of PD-L1 mRNA was detected by quantitative real-time PCR (qRT-PCR), and the expressions of PD-L1 and eIF5B proteins were observed by western blot assays. Cell Counting Kit-8 (CCK-8), flow cytometry, Transwell and Transwell martrigel were used to investigated cell proliferation, apoptosis, migration and invasion, respectively. The effect of peripheral blood mononuclear cells (PBMCs) on tumor cells was observed, and the interaction between eIF5B and Wig1 was revealed by co-immunoprecipitation (CoIP) assay. Finally, the effects of interference with eIF5B expression on the growth, morphology, and immunity of the tumor, as well as PD-L1 expression in the tumor, were verified by tumor xenograft assays in vivo.ResultsCompared with normal prostate epithelial cells, prostate cancer cells revealed higher expressions of eIF5B and PD-L1 interference with eIF-5B expression can inhibit the proliferation, migration, invasion and PD-L1 expression of prostate cancer cells. Meanwhile, the cancer cell group with interference with eIF5B expression also demonstrated greater, apoptosis and higher vulnerability to PBMCs. CoIP assays showed that Wig1 could bind to eIF5B in prostate cancer cells, and its overexpression can inhibit the proliferation, migration, invasion and PD-L1 expression of cancer cells while promoting apoptosis. Moreover, interference with eIF5B expression can inhibit tumor growth, destroy tumor morphology, and suppress the proliferation of tumor cells.ConclusioneIF5B can promote the expression of PD-L1 by interacting with Wig1. Besides, interference with eIF5B expression can inhibit the proliferation, migration, invasion and immunosuppressive response of prostate cancer cells. This study proposes a new target, eIF5B, for immunotherapy of prostate cancer.

Dataset Information

EIF5B drives integrated stress response-dependent translation of PD-L1 in lung cancer.

Publications

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

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