The tumor preventive effect of polyIC and the importance of Toll-like receptor-mediated signal transduction in hepatocarcinogenesis

随着atezolizumab与抗血管生成药物贝伐单抗（bevacizumab）联合获批，免疫肿瘤学治疗肝细胞癌（HCC）的时代开始于2020年。尽管取得了这一成功，但HCC的治疗效果与黑色素瘤和肺癌等免疫热点肿瘤的治疗效果相比并不理想。因此，为了释放免疫检查点抑制在HCC中的全部潜力，需要免疫增敏策略，例如polyIC的应用。圣地亚哥的冯教授领导的研究小组成功地证明了这种rna -聚合物在与PD-L1抗体联合治疗中的协同作用。此外，他们还发现，基于适应性免疫和先天免疫之间复杂的相互作用，polyIC具有预防肿瘤的作用。polyIC可能的效应物包括toll样受体TLR3和TLR9，随后激活CD8+ T细胞。该项目的总体目标是破译polyIC的确切作用机制，从而为HCC的肿瘤预防治疗的转化发展做出贡献。为了实现这一点，打算使用肝细胞移植模型。脾注射由polyIC /对照处理小鼠产生的供肝细胞，可以通过在受体动物肝脏中产生肿瘤来比较分析肿瘤起始细胞。此外，将采用癌基因水动力基因转移的方法来表征polyIC对toll样受体敲除小鼠的影响。此外，将对实验组内的肿瘤起始细胞、瘤前病变和肿瘤进行RNAseq和体外分析。通过这种方法，可以确定polyIC的效应物，这些效应物可能代表精确肿瘤学的潜在治疗靶点。

The era of immunooncology in hepatocellular carcinoma (HCC) began in 2020 with the approval of atezolizumab in combination with the antiangiogenic drug bevacizumab. Depsite this success, the treatment efficiency in HCC compares unfavorably with the results obtained in immunologically hot tumors such as melanoma and lung cancer. Therefore, to unleash the full potential of immune-checkpoint inhibition in HCC, strategies for immune sensitization are required, as for example the application of polyIC. The research group around the host professor Feng in San Diego managed to demonstrate the synergistic effect of this RNA-polymer in a combination therapy with PD-L1 antibodies. Moreover, they discovered a tumor-preventive role of polyIC based on an intricate interplay between adaptive and innate immunity. Possible effectors of polyIC include Toll-like receptors TLR3 and TLR9 with a subsequent activation of CD8+ T cells. The overarching aim of this project is to decipher the exact mechanism of action of polyIC and thereby to contribute to the translational development of tumor preventive therapies in HCC.To achieve this, a hepatocyte-transplantation model is intended to be used. The splenic injection of donor-hepatocytes generated from polyIC-/ control-treated mice allows for the comparative analysis of tumor initiating cells via the generation of tumors in the recipient animals' livers. Furthermore, the method of oncogene hydrodynamic gene transfer will be employed to characterize the effect of polyIC in Toll-like receptor knockout mice. In addition, RNAseq and in vitro analyses will be performed on tumor-initiating cells, preneoplastic lesions and tumors within the experimental groups. By this means the effectors of polyIC shall be identified, which could potentially represent therapeutic targets in precision oncology.