The Efficacy of Immunotherapy in Preventing Liver Cancer and the Role of Metabolic Zonation in Its Development

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August 2021

Authors

Chung, Andrew Seungjae

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Abstract

In order to study the development and progression of liver cancer, as well as the efficacy of novel therapeutic strategies, accurate models of human disease are needed. In particular, in vivo mouse models capture critical characteristics that are relevant to human hepatocellular carcinoma (HCC). There is a diverse array of mouse HCC models available, falling into three major categories: transplantation-based models, chemically-induced models, and genetically-induced models. Within these categories, models differ in factors such as the source of the tumor cells and the chemicals or genetic drivers used to induce tumorigenesis. All of these models offer specific advantages over the others but also have some disadvantages as well. Thus, the utility of any model is dependent on the specific investigatory aims of the study. In our case, we used two types of models to try to address two questions about HCC. First, we asked if immune checkpoint inhibition could prevent tumorigenesis in a chemically-induced mouse model of HCC. We found that initiation of anti-PD-1 immunotherapy prior to tumorigenesis could prevent up to 46% of liver tumors. This reduction in tumor burden was accompanied by infiltration of CD4+ T helper and CD8+ cytotoxic T cells into the liver parenchyma. Importantly, anti-PD-1 therapy did not exacerbate liver dysfunction or worsen overall health in this model. Given the safety and preservation of quality of life observed with long-term immunotherapy use, an immunotherapy chemoprevention strategy is likely associated with a low risk-to-benefit ratio and high value care in select patients. Along the portal-to-central axis within the hepatic lobule, there are profound differences in gene expression, metabolic processes, oxygen tension, and ploidy. Whether or not these differences reflect any differences in neoplastic potential is unclear. To address this, we turned to genetically-induced HCC models. We used various hepatic zone-specific CreERT2 mouse lines to induce activating mutations in Ctnnb1 and to delete Arid2. We found that mutant clones arising from zone 1 gradually expanded and persisted, while mutant clones arising from Zone 3 rapidly disappeared over time. However, more tumors ultimately developed in the zone 3 livers than in the zone 1 livers, suggesting that expression of some zonated metabolic genes may influence the fate of mutant hepatocytes. This could have major implications for prevention and treatment of HCC, as these metabolic genes could represent actionable preventive or therapeutic targets.

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