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Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib

BACKGROUND: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen inje...

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Autores principales: Yang, Yang, Sun, Mayu, Yao, Wenbo, Wang, Feng, Li, Xiaoguang, Wang, Wei, Li, Jingquan, Gao, Zhihu, Qiu, Lin, You, Rongli, Yang, Chenghua, Ba, Qian, Wang, Hui
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073790/
https://www.ncbi.nlm.nih.gov/pubmed/32179631
http://dx.doi.org/10.1136/jitc-2019-000317
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author Yang, Yang
Sun, Mayu
Yao, Wenbo
Wang, Feng
Li, Xiaoguang
Wang, Wei
Li, Jingquan
Gao, Zhihu
Qiu, Lin
You, Rongli
Yang, Chenghua
Ba, Qian
Wang, Hui
author_facet Yang, Yang
Sun, Mayu
Yao, Wenbo
Wang, Feng
Li, Xiaoguang
Wang, Wei
Li, Jingquan
Gao, Zhihu
Qiu, Lin
You, Rongli
Yang, Chenghua
Ba, Qian
Wang, Hui
author_sort Yang, Yang
collection PubMed
description BACKGROUND: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib. METHODS: Growth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8(+) T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8(+) T cells. RESULTS: CKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8(+) T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells. CONCLUSIONS: CKI acts on macrophages and CD8(+) T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment.
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spelling pubmed-70737902020-03-20 Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib Yang, Yang Sun, Mayu Yao, Wenbo Wang, Feng Li, Xiaoguang Wang, Wei Li, Jingquan Gao, Zhihu Qiu, Lin You, Rongli Yang, Chenghua Ba, Qian Wang, Hui J Immunother Cancer Clinical/Translational Cancer Immunotherapy BACKGROUND: There is an urgent need for effective treatments for hepatocellular carcinoma (HCC). Immunotherapy is promising especially when combined with traditional therapies. This study aimed to investigate the immunomodulatory function of an approved Chinese medicine formula, compound kushen injection (CKI), and its anti-HCC efficiency in combination with low-dose sorafenib. METHODS: Growth of two murine HCC cells was evaluated in an orthotopic model, a subcutaneous model, two postsurgical recurrence model, and a tumor rechallenge model with CKI and low-dose sorafenib combination treatment. In vivo macrophage or CD8(+) T cell depletion and in vitro primary cell coculture models were used to determine the regulation of CKI on macrophages and CD8(+) T cells. RESULTS: CKI significantly enhanced the anticancer activity of sorafenib at a subclinical dose with no obvious side effects. CKI and sorafenib combination treatment prevented the postsurgical recurrence and rechallenged tumor growth. Further, we showed that CKI activated proinflammatory responses and relieved immunosuppression of tumor-associated macrophages in the HCC microenvironment by triggering tumor necrosis factor receptor superfamily member 1 (TNFR1)-mediated NF-κB and p38 MAPK signaling cascades. CKI-primed macrophages significantly promoted the proliferation and the cytotoxic ability of CD8(+) T cells and decreased the exhaustion, which subsequently resulted in apoptosis of HCC cells. CONCLUSIONS: CKI acts on macrophages and CD8(+) T cells to reshape the immune microenvironment of HCC, which improves the therapeutic outcomes of low-dose sorafenib and avoids adverse chemotherapy effects. Our study shows that traditional Chinese medicines with immunomodulatory properties can potentiate chemotherapeutic drugs and provide a promising approach for HCC treatment. BMJ Publishing Group 2020-03-15 /pmc/articles/PMC7073790/ /pubmed/32179631 http://dx.doi.org/10.1136/jitc-2019-000317 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://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/.
spellingShingle Clinical/Translational Cancer Immunotherapy
Yang, Yang
Sun, Mayu
Yao, Wenbo
Wang, Feng
Li, Xiaoguang
Wang, Wei
Li, Jingquan
Gao, Zhihu
Qiu, Lin
You, Rongli
Yang, Chenghua
Ba, Qian
Wang, Hui
Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib
title Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib
title_full Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib
title_fullStr Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib
title_full_unstemmed Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib
title_short Compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through TNFR1 and sensitizes hepatocellular carcinoma to sorafenib
title_sort compound kushen injection relieves tumor-associated macrophage-mediated immunosuppression through tnfr1 and sensitizes hepatocellular carcinoma to sorafenib
topic Clinical/Translational Cancer Immunotherapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073790/
https://www.ncbi.nlm.nih.gov/pubmed/32179631
http://dx.doi.org/10.1136/jitc-2019-000317
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