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FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer
BACKGROUND: Activation of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been extensively described as a pivotal mechanism to escape immune surveillance and elicits suppressive effect on antitumor immunity. Blockade of the PD-1/PD-L1 interaction by checkpoint...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476142/ https://www.ncbi.nlm.nih.gov/pubmed/36104103 http://dx.doi.org/10.1136/jitc-2022-005116 |
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author | Liu, Jiaxin Wei, Lingyun Hu, Nan Wang, Dong Ni, Juan Zhang, Sha Liu, Hongbing Lv, Tangfeng Yin, Jie Ye, Mingxiang Song, Yong |
author_facet | Liu, Jiaxin Wei, Lingyun Hu, Nan Wang, Dong Ni, Juan Zhang, Sha Liu, Hongbing Lv, Tangfeng Yin, Jie Ye, Mingxiang Song, Yong |
author_sort | Liu, Jiaxin |
collection | PubMed |
description | BACKGROUND: Activation of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been extensively described as a pivotal mechanism to escape immune surveillance and elicits suppressive effect on antitumor immunity. Blockade of the PD-1/PD-L1 interaction by checkpoint inhibitors has been shown to result in tumor shrinkage and prolong patient survival. However, regulatory machinery for PD-1/PD-L1 expression is largely unknown. METHODS: We used bioinformatic tools and biochemical methods to investigate the significance of F-box and WD repeat domain containing 7 (FBW7) in regulating PD-1 protein stability. By generating a panel of FBW7 and PD-1 encoding plasmids, we expressed FBW7 and PD-1 or their mutants to performed immunoprecipitation and immunoblotting assays. The efficacy of cotargeting FBW7 to enhance antitumor immunity was evaluated in C57BL/6J mice. These laboratory findings were further validated in tumor samples obtained from patients with non-small cell lung cancer (NSCLC). RESULTS: We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. Cotargeting FBW7 accelerates PD-1 protein degradation and enhances antitumor immunity in vivo. Moreover, we demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. Higher expression of FBW7 characterizes a ‘hot’ tumor microenvironment and confers more favorable responses to PD-1 blockade therapy. CONCLUSIONS: This study highlights the critical role of FBW7 in determining PD-1 protein stability. FBW7 ubiquitinates PD-1 in a phosphorylation-dependent manner, as a consequence, leading to PD-1 protein degradation and cytotoxic lymphocytes infiltrating the tumor microenvironment. Screening FBW7 status would predict clinical response to anti-PD-1 immunotherapy in patients with NSCLC, and targeting FBW7 is a promising strategy to enhance antitumor immunity. |
format | Online Article Text |
id | pubmed-9476142 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-94761422022-09-16 FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer Liu, Jiaxin Wei, Lingyun Hu, Nan Wang, Dong Ni, Juan Zhang, Sha Liu, Hongbing Lv, Tangfeng Yin, Jie Ye, Mingxiang Song, Yong J Immunother Cancer Basic Tumor Immunology BACKGROUND: Activation of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway has been extensively described as a pivotal mechanism to escape immune surveillance and elicits suppressive effect on antitumor immunity. Blockade of the PD-1/PD-L1 interaction by checkpoint inhibitors has been shown to result in tumor shrinkage and prolong patient survival. However, regulatory machinery for PD-1/PD-L1 expression is largely unknown. METHODS: We used bioinformatic tools and biochemical methods to investigate the significance of F-box and WD repeat domain containing 7 (FBW7) in regulating PD-1 protein stability. By generating a panel of FBW7 and PD-1 encoding plasmids, we expressed FBW7 and PD-1 or their mutants to performed immunoprecipitation and immunoblotting assays. The efficacy of cotargeting FBW7 to enhance antitumor immunity was evaluated in C57BL/6J mice. These laboratory findings were further validated in tumor samples obtained from patients with non-small cell lung cancer (NSCLC). RESULTS: We identified FBW7 as a E3 ubiquitin ligase for PD-1 protein, in which FBW7 promotes the K48-linked polyubiquitination of PD-1 protein at Lys233 residue. Cotargeting FBW7 accelerates PD-1 protein degradation and enhances antitumor immunity in vivo. Moreover, we demonstrated that cyclin-dependent kinase 1-mediated phosphorylation of Ser261 residue primes PD-1 protein nucleus translocation and binding with FBW7. Higher expression of FBW7 characterizes a ‘hot’ tumor microenvironment and confers more favorable responses to PD-1 blockade therapy. CONCLUSIONS: This study highlights the critical role of FBW7 in determining PD-1 protein stability. FBW7 ubiquitinates PD-1 in a phosphorylation-dependent manner, as a consequence, leading to PD-1 protein degradation and cytotoxic lymphocytes infiltrating the tumor microenvironment. Screening FBW7 status would predict clinical response to anti-PD-1 immunotherapy in patients with NSCLC, and targeting FBW7 is a promising strategy to enhance antitumor immunity. BMJ Publishing Group 2022-09-14 /pmc/articles/PMC9476142/ /pubmed/36104103 http://dx.doi.org/10.1136/jitc-2022-005116 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) . |
spellingShingle | Basic Tumor Immunology Liu, Jiaxin Wei, Lingyun Hu, Nan Wang, Dong Ni, Juan Zhang, Sha Liu, Hongbing Lv, Tangfeng Yin, Jie Ye, Mingxiang Song, Yong FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer |
title | FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer |
title_full | FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer |
title_fullStr | FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer |
title_full_unstemmed | FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer |
title_short | FBW7-mediated ubiquitination and destruction of PD-1 protein primes sensitivity to anti-PD-1 immunotherapy in non-small cell lung cancer |
title_sort | fbw7-mediated ubiquitination and destruction of pd-1 protein primes sensitivity to anti-pd-1 immunotherapy in non-small cell lung cancer |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9476142/ https://www.ncbi.nlm.nih.gov/pubmed/36104103 http://dx.doi.org/10.1136/jitc-2022-005116 |
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