CUHK unveils the key to liver cancer immunotherapy resistance, identifies the “clear out-feed in” function of macrophages that fuels cancer cells
Immunotherapy has recently become the first-line treatment for advanced liver cancer. However, most patients with advanced liver cancer exhibit resistance to immunotherapy. For years, the medical profession has been striving to uncover the mechanisms behind this resistance, with the hope of finding breakthroughs for those who do not benefit from immunotherapy. A research study from The Chinese University of Hong Kong (CUHK)’s Faculty of Medicine (CU Medicine) has further discovered the mechanisms of liver cancer immunotherapy resistance. The research revealed a novel “clear out–feed in” function of the macrophage subtype “TREM2+ LAM”, which provides nutrients to cancer cells during the process of clearing apoptotic cells (efferocytosis). This discovery may serve as a new drug target for the immunotherapy of liver cancer. The research team has applied for a patent for “TREM2+ LAM” as a therapeutic approach and plans to conduct clinical studies to develop novel combination therapy. The findings have been published in the internationally renowned scientific journal, Cancer Cell.
CU Medicine has further discovered the mechanisms of liver cancer immunotherapy resistance. The research revealed a novel “clear out–feed in” function of the macrophage subtype “TREM2+ LAM”, which provides nutrients to cancer cells during the process of clearing apoptotic cells. This discovery may serve as a new drug target for the immunotherapy of liver cancer.
(From left) Professor Stephen Chan Lam, Ip’s Family Trust Professor in Clinical Oncology and Professor of the Department of Clinical Oncology atCU Medicine; Dr Liang Zhixian, Post-doctoral Fellow, School of Biomedical Sciences at CU Medicine; and Professor Alfred Cheng Sze-lok, Professor from the School of Biomedical Sciences at CU Medicine.
Liver cancer is the third leading cause of cancer-related deaths in Hong Kong, with most patients diagnosed at an advanced stage. For tumours that cannot be removed surgically, immunotherapy is commonly used as a first-line treatment. However, even with a good initial response, over 80% of patients will eventually develop resistance to immunotherapy. While it is well known that tumour cells can adapt to the nutrient-deprived tumour microenvironment, the mechanism by which they evade immune checkpoint blockade (ICB) and develop resistance to immunotherapy remains unclear.
In 2023, a research team led by Professor Alfred Cheng Sze-lok from the School of Biomedical Sciences (SBS) at CU Medicine, revealed that liver cancer cells can adapt to immunotherapy, resulting in resistance to ICB, the most commonly used therapy for liver cancer. Building on these foundational research findings, the team’s latest study further discovered that a type of macrophage known as TREM2+ LAM not only removes apoptotic cells but also provides nutrients to tumour cells during the process. This "feed-in" function helps tumours resist immune cell attack and is a key factor contributing to resistance against ICB therapy.
Unveiling how TREM2+ LAM drives immunotherapy resistance in cancer cells
A research team led by Professor Alfred Cheng has revealed a novel “clear out–feed in” function of the macrophage subtype TREM2+ LAM. These cells “recycle” fatty acids from apoptotic cells in the tumour microenvironment and transport them via extracellular vesicles to cancer cells, providing nutrients and reprogramming gene expression within the tumour. This process helps tumour cells resist immune attack and increases their resistance to immunotherapy.
Macrophages act as the body’s “street sweepers”, responsible for removing foreign particles, bacteria, and dead or apoptotic cells. They are highly adaptable, capable of transforming into different phenotypes in response to environmental signals and initiating subsequent immune responses. A study from the team found that in most liver cancer patients treated with PD-1 inhibitors (a type of ICB therapy), TREM2+ LAM increases within the tumour and is significantly associated with poor prognosis of patients undergoing anti-PD-1 therapy, highlighting its clinical significance.
By analysing tumour cells from liver cancer patients who did not respond to anti-PD-1 therapy, the team found that these tumour cells exhibited highly active fatty acid metabolism. Further studies in mouse models revealed that, within the metabolically demanding tumour microenvironment, TREM2+ LAM appears as a macrophage subtype with strong lipid-processing capabilities. It "recycles" fatty acids from apoptotic cells and transports them via extracellular vesicles to cancer cells, providing nutrients and reprogramming gene expression in the tumour. This process helps tumour cells resist immune attack and enhances their resistance to immunotherapy.
Patent filed for TREM2+ LAM as a therapy
Dr Liang Zhixian, Post-doctoral Fellow, School of Biomedical Sciences, CU Medicine, remarked: “Building on these findings, our team conducted further experiments in mice. In cancer-bearing mice that were originally unresponsive to immunotherapy, a combination therapy of PD-1 inhibitor and TREM2 inhibitor was administered. After four weeks, the tumours in the mice were significantly reduced in size, and no behavioural changes or side effects related to body weight were observed, suggesting that this combination immunotherapy is safe and effective.”
Professor Alfred Cheng Sze-lok said: “We have applied for a patent on the use of TREM2+ LAM in immunotherapy. Our team is currently in discussions with pharmaceutical sector to prepare for clinical studies, aiming to confirm the efficacy and safety of combination immunotherapy targeting TREM2+ LAM as a precision treatment. We expect to have results in two to three years.”
Professor Stephen Chan Lam, Ip’s Family Trust Professor of Clinical Oncology in Clinical Oncology and Professor of the Department of Clinical Oncology at CU Medicine, stated: “These research findings are encouraging and suggest that combination immunotherapy targeting TREM2+ LAM could bring new hope to patients who currently do not benefit from immunotherapy. It is estimated that this approach could benefit up to 40% to 50% of liver cancer patients. Not only does this offer the prospect of prolonging the lives of patients with advanced liver cancer, but it may also be applicable to other types of cancers with high levels of TREM2+ LAM, allowing more people to benefit from immunotherapy.”
Professor Alfred Cheng says that in the future, liver cancer patients will be asked to take a blood sample for testing; if the proportion of TREM2+ is high, a combination therapy using a TREM2+ LAM inhibitor and a PD-1 antibody can be administered. This treatment strategy has already been patented, and the team plans to conduct clinical studies to further develop this novel combination therapy.
Professor Stephen Chan remarks liver cancer is the third leading cause of cancer-related deaths in Hong Kong. This research finding brings new hope to patients who are currently unable to benefit from immunotherapy; not only does it have the potential to prolong the lives of patients with advanced liver cancer, but it may also be applied to other cancers with a high presence of TREM2+ LAM, such as triple-negative breast cancer and non-small cell lung cancer, allowing more people to benefit from immunotherapy.
