Editor’s Note:
Liver cancer is the third leading cause of cancer death in China. In recent years, the application of targeted and immunotherapies has improved the survival of liver cancer patients. However, due to the high molecular heterogeneity of liver cancer, there is still a lack of biological markers for predicting clinical efficacy, and there is a significant difference in treatment responses among liver cancer patients. From July 6th to 8th, 2023, the 13th Asia-Pacific Primary Liver Cancer Experts Conference (APPLE 2023) was grandly held in Seoul, South Korea. At the conference, Dr. Irene Oi-Lin Ng from the University of Hong Kong, China, shared recent advancements in the study of liver cancer’s molecular heterogeneity and its biological markers, offering new insights into the development of novel clinical treatment strategies and precise drug efficacy predictions for personalized precision diagnosis and treatment. Hepatology Digest had an in-depth interview with Dr. Ng at the APPLE conference.
Hepatology Digest: Can you share about recent clinical research predicting factors that might predict the prognosis of hepatocellular carcinoma?
Dr. Ng: In recent years, some clinical studies have emerged concerning the prognosis prediction of liver cancer. Many studies have indicated positive predictive factors that will be beneficial for future clinical predictions. For example, it’s found that an increase in CD8 positive T cells in liver cancer tissue can help predict its prognosis. Many molecules within the tissue can also be used for prognosis prediction, like hypoxia-related genes, HIF1α-related genes, etc.
Recently, our research team used a large number of clinical samples and conducted single-cell RNA sequencing on over 18,000 liver cancer cells. It was found that tumor-associated macrophages inhibited the T cells’ penetration of tumors, and T cells are crucial in fighting cancer cells. Researchers identified a new immune checkpoint axis—TIGIT-NECTIN2—that regulates the immune-suppressive environment. Further research found that TIGIT-NECTIN2 causes immune cells to gradually lose their immunity within the tumor, thus promoting liver cancer. This means that by inhibiting the TIGIT-NECTIN2 immune checkpoint axis, we could potentially restore the immune system’s attack on cancer cells, offering more effective precision treatments for liver cancer patients.
Hepatology Digest: Due to the molecular heterogeneity of liver cancer, patients at the same clinical stage often have different clinical outcomes. How can we better stratify these patients? Can you share the latest advancements in this area?
Dr. Ng: I believe that this involves stratifying patients not just based on prognosis but also on their treatment responses.
Admittedly, many recent studies have focused on using biological markers to stratify patient treatment responses. However, unfortunately, currently, there’s only one molecular marker that can effectively predict a negative response, and that’s the activation of the Wnt/β-catenin pathway in tumors. Studies show that the activation of the Wnt/β-catenin signal is related to immune rejection, leading to resistance to immunotherapy in liver cancer patients. This is the only evidence-based medical result at present, while other potential biological markers haven’t made much progress. So far, no single predictive biological marker has been used to stratify liver cancer patients. We hope that with the relentless efforts of scientists worldwide in finding predictive biological markers, we will soon see the dawn.
Hepatology Digest: Could you introduce us to the main research achievements of your team in recent years and their clinical significance?
Dr. Ng: My primary research focus is on the molecular and cytological mechanisms of hepatocellular carcinoma. Over the past twenty years, our team’s work has mainly focused on the molecular markers of tumor-initiating cells (T-IC), which are key cells causing liver cancer growth and recurrence. As mentioned before, our team has recently been using cutting-edge techniques (single-cell RNA sequencing and omics analysis, as well as spatial transcriptomics) to analyze liver cancer prognosis-related biological markers, analyzing key gene mutations, drivers, and signaling pathways controlling hepatocellular carcinoma. Recently, our team also published an article about the PD-1 inhibitor (nivolumab monoclonal antibody) as a neoadjuvant treatment before liver cancer surgery, aiming to find pathological and biological markers that influence patient treatment responses, thus better guiding clinical treatment of liver cancer.
