HCC immunology: correlating immune profiles to specific response to immunotherapy

点击翻译按钮获取中文摘要

Liver cancer is one of the few malignancies with both rising mortality and incidence and the second leading cause of cancer related mortality worldwide. As still, almost half of the patients with HCC are not diagnosed until advanced stages of the disease, curative treatments such as resection and transplantation are only available for a limited amount of patients. Currently, the only systemic therapy available is the multi-tyrosine kinase inhibitor sorafenib alongside lenvatinib and regorafenib with limited survival benefit.Accordingly there is a substantial need for improving the therapeutic options for these patients.This project includes three lines of inquiry:First, this project aims at deciphering molecular elements that determine cancer immunity in HCC. This is based on the fact that, despite promising results in animal models, several clinical trials have failed to elicit a survival benefit using various checkpoint-inhibitors. Criticism of these trials has largely focused on the generalised treatment approaches.Therefore, understanding the interplay between cancer cells and the microenvironment, mechanisms determining tumor immunogenicity of the recently described immune profiles and how they correlate to specific responses to therapy is of critical importance.Second, by thoroughly characterizing the composition of tumor tissue and paired peripheral blood immune cells and cytokines, non-invasive tools could, through this project, be provided for the identification of patients belonging to the distinct HCC immune profiles. In addition, mutant circulating tumor DNA will be assessed as a tool to track candidate drivers of response or resistance to immunotherapies.Third, a genetically engineered mouse model capable of mimicking HCC immune profiles will be generated in this project. Subsequently, mice with different profiles will be exposed to various immunotherapies in order to further explore therapeutic strategies and increase the efficacy of currently available immunotherapies.