KAIST "Elucidation of Liver Cancer Onset Mechanism... Proposing a New 'Therapeutic Target'"

A domestic research team has elucidated the mechanism of liver cancer development and proposed a new therapeutic target.

Liver cancer accounts for about 3% of all cancer incidence. Currently, clinical trials using various therapeutic drugs are underway, among which immune checkpoint inhibitors are commonly used. However, due to low response rates and high incidence of adverse events, more effective therapeutic targets have been demanded. This highlights the significance of proposing new therapeutic targets.

KAIST announced on the 8th that Professor Jeong Won-il's research team at the Graduate School of Medical Science and Engineering identified the metabolic interaction between tumor-associated macrophages and hepatic stellate cells as a pathogenic mechanism of liver cancer that suppresses the proliferation of cytotoxic CD8+ T cells, proposing this as a new therapeutic target for liver cancer.

Professor Jeong Won-il. Provided by KAIST

First, the research team confirmed that a specific tumor-associated macrophage expressing the signaling molecule CX3CR1 chemokine, which plays an important role in macrophage infiltration, migrates into the fibrotic cancer-surrounding tissue and interacts with activated hepatic stellate cells.

At this time, retinoic acid secreted from the activated hepatic stellate cells induces the expression of arginase 1 (hereafter Arg1) in tumor-associated macrophages, promoting arginine metabolism, which suppresses the proliferation of cytotoxic CD8+ T cells while increasing liver cancer development, according to the research team.

Additionally, single-cell genomic analysis using liver tissue from liver cancer patients identified a specific macrophage cluster expressing CX3CR1 and Arg1 within the tumor microenvironment, and these macrophages were found to be in close proximity to activated hepatic stellate cells.

Notably, the research team reported that when liver cancer was induced in CX3CR1-deficient mice using carcinogens, the number of tumor-associated macrophages migrating to the cancer-surrounding tissue decreased, and tumor occurrence was significantly reduced.

During cancer development, various immune cells exist within the tumor microenvironment, and cytotoxic CD8+ T cells induce anti-cancer immune responses that suppress tumor formation.

However, when arginine, necessary for CD8+ T cell proliferation, is depleted due to macrophage Arg1, the reduction of CD8+ T cell clusters and the consequent decrease in anti-cancer immune responses lead to tumor development.

This Arg1 expression in macrophages is induced by retinoic acid derived from adjacent hepatic stellate cells, and the study confirmed that inhibiting retinol metabolism in hepatic stellate cells in mice improved liver cancer.

Through this, the research team revealed for the first time the metabolic mechanism of interaction between immune cells and non-parenchymal hepatic stellate cells within the liver cancer tumor microenvironment, and based on the improvement of liver cancer upon inhibition of this interaction, proposed a new strategy for liver cancer treatment.

Professor Jeong said, “By elucidating the intercellular interaction mechanism in the tumor microenvironment, our research team has for the first time suggested the possibility of controlling liver cancer progression,” adding, “If the therapeutic target proposed by our team is used together with existing immune checkpoint inhibitors, a dramatic therapeutic effect on liver cancer occurrence can be expected.”

Meanwhile, this study, co-first authored by Dr. Jeong Jong-min and PhD candidate Choi Sung-eun from KAIST Graduate School of Medical Science and Engineering, was published online on July 19 in the world-renowned international journal Hepatology. This research was conducted with support from the Ministry of Science and ICT through the National Research Foundation’s Leading Research and Bio-Medical Technology Development programs.