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

PolyIC的肿瘤预防作用及Toll样受体介导的信号转导在肝癌发生中的重要性

• 批准号: 502688960
• 负责人: Dr. Alexander Scheiter
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2022
• 资助国家: 德国
• 起止时间: 2021-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/502688960?language=en
• 关键词: tumor; preventive; effect; polyIC; importance

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.

2020年，atezolizumab联合抗血管生成药物贝伐珠单抗获批，开启了肝细胞癌（HCC）的免疫肿瘤学时代。尽管取得了这一成功，但HCC的治疗效率与免疫学热点肿瘤（如黑色素瘤和肺癌）的治疗效果相比并不理想。因此，为了释放HCC中免疫检查点抑制的全部潜力，需要免疫致敏的策略，例如应用polyIC。圣地亚哥的主持人Feng教授周围的研究小组设法证明了这种RNA聚合物在与PD-L1抗体联合治疗中的协同作用。此外，他们发现了基于适应性免疫和先天免疫之间复杂相互作用的polyIC的肿瘤预防作用。polyIC的可能效应物包括Toll样受体TLR 3和TLR 9，随后激活CD 8 + T细胞。本项目的首要目标是破译polyIC的确切作用机制，从而有助于HCC肿瘤预防治疗的转化发展。从多聚IC-/对照处理的小鼠产生的供体肝细胞的脾注射允许通过受体动物肝脏中肿瘤的产生对肿瘤起始细胞进行比较分析。此外，还将采用癌基因流体动力学基因转移的方法来表征polyIC在Toll样受体敲除小鼠中的作用。此外，将对实验组内的肿瘤起始细胞、肿瘤前病变和肿瘤进行RNAseq和体外分析。通过这种方式，将识别polyIC的效应物，其可能代表精确肿瘤学中的治疗靶点。