Role of liver microbiome and immune-related biomarkers in predicting response to immunotherapy in hepatocellular carcinoma.

• Applicant: Dr. Marcus Zeitlhöfler
• Subject Area: Gastroenterology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 531006414

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer mortality worldwide More than 50% of patients require systemic treatment, and the combination of the immune checkpoint inhibitor (ICI) atezolizumab with bevacizumab (atezo+bev) is the new standard of care in the first-line treatment of advanced HCC. However, only about 30% of patients present survival benefits. Thus, there is an urgent need to a) uncover the differences in immunogenomic mechanisms of response and resistance to ICIs and b) identify biomarkers that predict response to immune therapies. In the majority of the cases, HCC develops in patients with cirrhosis, a condition for which the leaky gut and dysbiosis have been described as prominent features. Indeed, bacteria have been reported in human tumors but how their presence modulates tumor progression and tumor responses to treatment is yet unclear. The overall goal of this proposal is a) to characterize the liver microbiome and assess whether it has an impact in determining responses to ICIs and b) to uncover the mechanisms and biomarkers underlying response or resistance to atezo+bev in HCC. The specific objectives are: 1] To understand the role of the liver microbiome in anti-tumor immunity in HCC and its impact on response to immunotherapy. 2] To determine the mechanisms of response and resistance to atezo+bev in viral and non-viral patients. 3] To identify etiology-dependent biomarkers that predict response and resistance to immunotherapy in human HCC. The group of Prof. Llovet in New York where I will be conducting this research project is ideally positioned to achieve these goals and has compelling data that support the feasibility of the study. First, the group has already presented data suggesting that mutations related to NASH are associated with poor response to ICIs. Second, the group has demonstrated the ability to collect large cohorts of human samples, and de facto Prof. Llovet leads an international consortium that has already collected 250 atezo+bev-treated samples for the current project. Third, the group has proven expertise in defining molecular traits and signatures that predict response or resistance to treatment. Overall, by understanding the processes underlying response and resistance to ICIs in general, and atezo+bev in particular, we expect to be able to identify biomarkers suitable for clinical management, and thereby contribute to moving the field toward a more personalized approach. Additionally, the identification of mechanisms of response/resistance to atezo+bev, will provide unprecedented insights for the development of novel treatments capable of eliciting antitumor responses in patients who do not respond to current therapies, and finally improve survival in HCC patients.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professor Dr. Josep M. Llovet