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

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The Combination of R848 with Sorafenib Enhances Antitumor Effects by Reprogramming the Tumor Immune Microenvironment and Facilitating Vascular Normalization in Hepatocellular Carcinoma
Advanced Science ( IF 14.3 ) Pub Date : 2023-04-21 , DOI: 10.1002/advs.202207650
Yuchao He _{1,

2} , Linlin Zhan _{1,

2} , Jian Shi ₃ , Manyu Xiao ₄ , Ran Zuo _{1,

2} , Chengmeng Wang _{1,

2} , Zhiyong Liu _{1,

2} , Wenchen Gong _{2,

5} , Liwei Chen _{1,

2} , Yi Luo _{1,

2} , Shaojun Zhang ₆ , Youwei Wang ₇ , Lu Chen _{2,

8} , Hua Guo _{1,

2}

Affiliation

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-FTH1^high 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.

中文翻译：

R848 与索拉非尼的组合通过重新编程肿瘤免疫微环境并促进肝细胞癌中的血管正常化来增强抗肿瘤作用

迫切需要与索拉非尼联合使用的新策略，以增强其在肝细胞癌（HCC）中的临床疗效并克服毒性。介绍了索拉非尼单独使用以及与新型免疫治疗剂 R848 联合使用的分子和免疫调节抗肿瘤作用。提出同基因 HCC 小鼠模型，以探索三种索拉非尼单独剂量、单独 R848 或其组合的体内抗肿瘤作用和安全性。R848在低亚临床剂量下即可显着增强索拉非尼的抗肿瘤活性，且无明显毒副作用。此外，联合疗法通过增加抗肿瘤巨噬细胞和中性粒细胞并防止免疫抑制信号传导来重新编程肿瘤免疫微环境。联合治疗促进经典 M1 巨噬细胞向 FTH1^高M1 巨噬细胞的转变。中性粒细胞/经典M1巨噬细胞和树突状细胞之间的密切相互作用促进肿瘤抗原呈递给T细胞，诱导细胞毒性CD8 ⁺ T细胞介导的抗肿瘤免疫。此外，低剂量索拉非尼单独或与 R848 联合使用，可使肿瘤脉管系统正常化，产生正反馈回路以支持抗肿瘤免疫环境。因此，联合疗法重新编程了HCC免疫微环境并使脉管系统正常化，提高了低剂量索拉非尼的治疗效果并最大程度地降低了毒性，这为HCC治疗提出了一种有前途的新型免疫疗法（R848）和靶向疗法（酪氨酸激酶抑制剂）联合策略。

更新日期：2023-04-21

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