Cargando…
Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma
Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with h...
Autores principales: | , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257027/ https://www.ncbi.nlm.nih.gov/pubmed/35812439 http://dx.doi.org/10.3389/fimmu.2022.876048 |
_version_ | 1784741246399414272 |
---|---|
author | Kong, Xiangyi Zheng, Zhiying Song, Guoxin Zhang, Zihao Liu, Hanyuan Kang, Junwei Sun, Guoqiang Sun, Guangshun Huang, Tian Li, Xiao Rong, Dawei Wang, Ke Tang, Weiwei Xia, Yongxiang |
author_facet | Kong, Xiangyi Zheng, Zhiying Song, Guoxin Zhang, Zihao Liu, Hanyuan Kang, Junwei Sun, Guoqiang Sun, Guangshun Huang, Tian Li, Xiao Rong, Dawei Wang, Ke Tang, Weiwei Xia, Yongxiang |
author_sort | Kong, Xiangyi |
collection | PubMed |
description | Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC. |
format | Online Article Text |
id | pubmed-9257027 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-92570272022-07-07 Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma Kong, Xiangyi Zheng, Zhiying Song, Guoxin Zhang, Zihao Liu, Hanyuan Kang, Junwei Sun, Guoqiang Sun, Guangshun Huang, Tian Li, Xiao Rong, Dawei Wang, Ke Tang, Weiwei Xia, Yongxiang Front Immunol Immunology Immunotherapy treatments, particularly immune checkpoint blockade, can result in benefits in clinical settings. But many pre-clinical and clinical studies have shown that resistance to anti-PD1 therapy frequently occurs, leading to tumor recurrence and treatment failure, including in patients with hepatocellular carcinoma (HCC). In this study, 10 patients with HCC were remedied with anti-PD1, and pre-treatment biopsy samples were sequenced for 289 nanostring panel RNA to compare responsive and non-responsive tumors to identify possible pretreatment biomarkers or targets of anti-PD1 therapeutic responses. Fortunately, the expression of β-Glucuronidase (GUSB) in the non-responding tumors was found to be remarkably higher than that in responding tumors. Results of the cell counting kit 8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU), transwell, wound healing test, and flow cytometry showed that GUSB facilitated proliferation, invasion, as well as migration of human HCC cells and downregulated PD-L1 expression by promoting miR-513a-5p. Additionally, as a GUSB inhibitor, amoxapine can reduce the progression of human HCC cells, and was an effective treatment for HCC and improved the sensitivity of anti-PD1 therapy. In summary, this study reveals that increased GUSB downregulates PD-L1 expression by promoting miR-513a-5p, leading to primary resistance to anti-PD1 treatment in HCC, and amoxapine enhances the sensitivity of anti-PD1 therapy by inhibiting GUSB, providing a new strategy and method for improving the efficacy of anti-PD1 therapy and bringing new prospects for therapy of HCC. Frontiers Media S.A. 2022-06-22 /pmc/articles/PMC9257027/ /pubmed/35812439 http://dx.doi.org/10.3389/fimmu.2022.876048 Text en Copyright © 2022 Kong, Zheng, Song, Zhang, Liu, Kang, Sun, Sun, Huang, Li, Rong, Wang, Tang and Xia https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Kong, Xiangyi Zheng, Zhiying Song, Guoxin Zhang, Zihao Liu, Hanyuan Kang, Junwei Sun, Guoqiang Sun, Guangshun Huang, Tian Li, Xiao Rong, Dawei Wang, Ke Tang, Weiwei Xia, Yongxiang Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma |
title | Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma |
title_full | Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma |
title_fullStr | Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma |
title_full_unstemmed | Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma |
title_short | Over-Expression of GUSB Leads to Primary Resistance of Anti-PD1 Therapy in Hepatocellular Carcinoma |
title_sort | over-expression of gusb leads to primary resistance of anti-pd1 therapy in hepatocellular carcinoma |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9257027/ https://www.ncbi.nlm.nih.gov/pubmed/35812439 http://dx.doi.org/10.3389/fimmu.2022.876048 |
work_keys_str_mv | AT kongxiangyi overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT zhengzhiying overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT songguoxin overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT zhangzihao overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT liuhanyuan overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT kangjunwei overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT sunguoqiang overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT sunguangshun overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT huangtian overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT lixiao overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT rongdawei overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT wangke overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT tangweiwei overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma AT xiayongxiang overexpressionofgusbleadstoprimaryresistanceofantipd1therapyinhepatocellularcarcinoma |