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Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation
BACKGROUND: Immune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approa...
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/PMC9115032/ https://www.ncbi.nlm.nih.gov/pubmed/35577504 http://dx.doi.org/10.1136/jitc-2021-003819 |
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author | Zhu, Lin Kuang, Xinwei Zhang, Guanxiong Liang, Long Liu, Dandan Hu, Bin Xie, Zuozhong Li, Hui Liu, Hong Ye, Mao Chen, Xiang Liu, Jing |
author_facet | Zhu, Lin Kuang, Xinwei Zhang, Guanxiong Liang, Long Liu, Dandan Hu, Bin Xie, Zuozhong Li, Hui Liu, Hong Ye, Mao Chen, Xiang Liu, Jing |
author_sort | Zhu, Lin |
collection | PubMed |
description | BACKGROUND: Immune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approaches with ICIs and revealing the underlying mechanisms are important goals for achieving rapid clinical transformation and application. METHODS: The effects on antitumor immunity activity of albendazole (ABZ) and the synergistic effects of ABZ with CD73 blockade were investigated in the melanoma B16F10 and the Lewis lung cancer tumor-bearing immune-competent mice models. The mechanism of ABZ reducing PD-L1 protein level through suppressing UBQLN4 was identified and validated through immunoprecipitation-mass spectrometry and molecular methods. Bioinformatics and anti-PD-1 therapy melanoma patients samples analysis were used to assess the level of UBQLN4/PD-L1 in the therapeutic efficacy of anti-PD-1 therapy. RESULTS: ABZ induces CD8(+) T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level. Mechanistically, we revealed that ABZ promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which was bound to PD-L1 and stabilized PD-L1 protein. Preclinically, genetic deletion or target inhibition of CD73 showed synergistic effects with ABZ treatment in the immune-competent mice models. Significantly, UBQLN4 and PD-L1 levels were higher in the tumor region of responders versus non-responders and correlated with better progression-free survival and overall survival in anti-PD-1 therapy melanoma patients. CONCLUSIONS: Our findings revealed a previously unappreciated role of ABZ in antitumor immunity by inducing ubiquitin-mediated PD-L1 protein degradation, identified predictors for assessing the therapeutic efficacy of anti-PD-1 therapy, and provided novel therapeutic possibility by combination treatment of ABZ and CD73 blockade in cancers. |
format | Online Article Text |
id | pubmed-9115032 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-91150322022-06-04 Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation Zhu, Lin Kuang, Xinwei Zhang, Guanxiong Liang, Long Liu, Dandan Hu, Bin Xie, Zuozhong Li, Hui Liu, Hong Ye, Mao Chen, Xiang Liu, Jing J Immunother Cancer Basic Tumor Immunology BACKGROUND: Immune checkpoint inhibitors (ICIs) have been increasingly used in patients with various cancers and have shown efficient therapeutic outcomes. However, fewer than 40% of cases across multiple cancer types show a response to ICIs. Therefore, developing more efficient combinational approaches with ICIs and revealing the underlying mechanisms are important goals for achieving rapid clinical transformation and application. METHODS: The effects on antitumor immunity activity of albendazole (ABZ) and the synergistic effects of ABZ with CD73 blockade were investigated in the melanoma B16F10 and the Lewis lung cancer tumor-bearing immune-competent mice models. The mechanism of ABZ reducing PD-L1 protein level through suppressing UBQLN4 was identified and validated through immunoprecipitation-mass spectrometry and molecular methods. Bioinformatics and anti-PD-1 therapy melanoma patients samples analysis were used to assess the level of UBQLN4/PD-L1 in the therapeutic efficacy of anti-PD-1 therapy. RESULTS: ABZ induces CD8(+) T cell activity and subsequent immunotherapy response associated with suppression of PD-L1 protein level. Mechanistically, we revealed that ABZ promotes ubiquitin-mediated degradation of PD-L1 via suppressing UBQLN4, which was bound to PD-L1 and stabilized PD-L1 protein. Preclinically, genetic deletion or target inhibition of CD73 showed synergistic effects with ABZ treatment in the immune-competent mice models. Significantly, UBQLN4 and PD-L1 levels were higher in the tumor region of responders versus non-responders and correlated with better progression-free survival and overall survival in anti-PD-1 therapy melanoma patients. CONCLUSIONS: Our findings revealed a previously unappreciated role of ABZ in antitumor immunity by inducing ubiquitin-mediated PD-L1 protein degradation, identified predictors for assessing the therapeutic efficacy of anti-PD-1 therapy, and provided novel therapeutic possibility by combination treatment of ABZ and CD73 blockade in cancers. BMJ Publishing Group 2022-05-16 /pmc/articles/PMC9115032/ /pubmed/35577504 http://dx.doi.org/10.1136/jitc-2021-003819 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Basic Tumor Immunology Zhu, Lin Kuang, Xinwei Zhang, Guanxiong Liang, Long Liu, Dandan Hu, Bin Xie, Zuozhong Li, Hui Liu, Hong Ye, Mao Chen, Xiang Liu, Jing Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation |
title | Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation |
title_full | Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation |
title_fullStr | Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation |
title_full_unstemmed | Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation |
title_short | Albendazole induces immunotherapy response by facilitating ubiquitin-mediated PD-L1 degradation |
title_sort | albendazole induces immunotherapy response by facilitating ubiquitin-mediated pd-l1 degradation |
topic | Basic Tumor Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9115032/ https://www.ncbi.nlm.nih.gov/pubmed/35577504 http://dx.doi.org/10.1136/jitc-2021-003819 |
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