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

Abstract

BackgroundThere 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.MethodsGrowth 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.ResultsCKI 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.ConclusionsCKI 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.

Research Status and Molecular Mechanism of the Traditional Chinese Medicine and Antitumor Therapy Combined Strategy Based on Tumor Microenvironment

“…Clinical studies on non-small-cell lung carcinoma (NSCLC) ( 82 ), hepatocellular carcinoma ( 83 ), and ovarian cancer ( 84 ) use compound preparations, including classic traditional formula Xuefu Zhuyu decoction ( 82 ) and listed compound herbal medicine Shenqi Fuzheng injection ( 83 ). During in vitro and in vivo studies, apart from observing the effects on tumor cell proliferation, the related signaling pathways were explored, including the NF-κB and p38 MAPK signaling cascades mediated by TNFR1 in hepatocellular carcinoma cells (compound Kushen injection) ( 85 ) and the AKT pathway in gastric cancer and pancreatic cancer cells (Astragalus polysaccharide) ( 86 , 87 ). YIV-906, which is based on PHY906 ( 88 ), is a clinical observation drug that ensures > 90% consistency in product quality ( 89 ).…”

Sophoridine suppresses lenvatinib‐resistant hepatocellular carcinoma growth by inhibiting RAS/MEK/ERK axis via decreasing VEGFR2 expression

“…Currently, the curative treatment for early‐stage HCC patients includes liver resection, liver transplantation and local ablation 6 . It is noted that most HCC patients are diagnosed with advanced stage which means they cannot undertake those treatments because of dysfunction of liver 7 . Alternatively, only two targeted therapies sorafenib and lenvatinib have been approved by Food and Drug Administration as the standard frontline treatments for advanced HCC patients 8 .…”

“…6 It is noted that most HCC patients are diagnosed with advanced stage which means they cannot undertake those treatments because of dysfunction of liver. 7 Alternatively, only two targeted therapies sorafenib and lenvatinib have been approved by Food and Drug Administration as the standard frontline treatments for advanced HCC patients. 8 Similar to sorafenib, lenvatinib is an orally multi-targeted tyrosine kinase inhibitor that selectively inhibits vascular endothelial growth factor receptors (VEGFR), fibroblast growth factor receptors (FGFR), platelet-derived growth factor receptor α (PDGFRα), KIT and RET.…”

Integrated bioinformatics analysis to decipher molecular mechanism of compound Kushen injection for esophageal cancer by combining WGCNA with network pharmacology

“…CKI mainly contains various anticancer ingredients, such as matrine and oxymatrine, which can inhibit the growth of tumour cells, overcome resistance to metastasis and multidrug resistance, and protect human immunity 8 . CKI has been utilized in clinical practice for decades to treat various solid tumour types, including liver cancer, breast cancer, gastric cancer, and other cancer types 8 , 9 . The analysis of medical data on 2,550 ESCA patients from 22 large-scale hospitals in China confirmed that CKI has been relatively widely used in the clinical treatment of ESCA of different severities 10 .…”