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

• Applicant: Dr. Alexander Scheiter
• Subject Area: Pathology ; Hematology, Oncology
• Term: from 2022 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 502688960

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.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Gen-Sheng Feng, Ph.D.