The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma

• Published in: Advanced science 2023-06, Vol.10 (18), p.e2207650-n/a
• Main Authors: He, Yuchao, Zhan, Linlin, Shi, Jian, Xiao, Manyu, Zuo, Ran, Wang, Chengmeng, Liu, Zhiyong, Gong, Wenchen, Chen, Liwei, Luo, Yi, Zhang, Shaojun, Wang, Youwei, Chen, Lu, Guo, Hua
• Format: Article
• Language: English
• Subjects: Animals; Carcinoma, Hepatocellular - drug therapy; Cytotoxicity; Drug dosages; FDA approval; hepatocellular carcinoma; Hypoxia; immune microenvironment; Immunotherapy; Kinases; Liver cancer; Liver Neoplasms - drug therapy; Medical prognosis; Mice; Neutrophils; Niacinamide - pharmacology; Niacinamide - therapeutic use; Phenylurea Compounds - pharmacology; Phenylurea Compounds - therapeutic use; R848; sorafenib; Sorafenib - pharmacology; Sorafenib - therapeutic use; Toxicity; Tumor Microenvironment; Tumors; vascular normalization
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202207650

Novel promising strategies for combination with sorafenib are urgently needed to enhance its clinical benefit and overcome toxicity in hepatocellular carcinoma (HCC). the molecular and immunomodulatory antitumor effects of sorafenib alone and in combination with the new immunotherapeutic agent R848 are presented. Syngeneic HCC mouse model is presented to explore the antitumor effect and safety of three sorafenib doses alone, R848 alone, or their combination in vivo. R848 significantly enhances the sorafenib antitumor activity at a low subclinical dose with no obvious toxic side effects. Furthermore, the combination therapy reprograms the tumor immune microenvironment by increasing antitumor macrophages and neutrophils and preventing immunosuppressive signaling. Combination treatment promotes classical M1 macrophage‐to‐FTH1high M1 macrophage transition. The close interaction between neutrophils/classical M1 macrophages and dendritic cells promotes tumor antigen presentation to T cells, inducing cytotoxic CD8+ T cell‐mediated antitumor immunity. Additionally, low‐dose sorafenib, alone or combined with R848, normalizes the tumor vasculature, generating a positive feedback loop to support the antitumor immune environment. Therefore, the combination therapy reprograms the HCC immune microenvironment and normalizes the vasculature, improving the therapeutic benefit of low‐dose sorafenib and minimizing toxicity, suggesting a promising novel immunotherapy (R848) and targeted therapy (tyrosine kinase inhibitors) combination strategy for HCC treatment. Combined treatment with low‐dose sorafenib and R848 reprograms the tumor immune microenvironment by increasing the population and activation of antitumor macrophages and neutrophils. These cells later activate dendritic cells, thus resulting in more efficient antigen presentation to T cells. TNF‐α secreted by T cells contributes to vascular normalization, which in turn supports immune cell infiltration, forming a positive feedback loop.