Professor Feng (Right 4), Professor Wang (Right 3), and the TRS Team

Professor Feng and Professor Wang, and the Postdoctoral Fellows of the Project

Poster Presentation by Postdoctoral Fellows and RPg Students of the Project

Professor Gen-Sheng Feng, from the University of California San Diego, and Professor Wang Peng (Representative of Professor Gao Qiang), from the Fudan University, visited HKU on 21 February 2025 as Scientific Advisory Board members for the TRS project - Delineating and Translating the Mechanistic Determinants to Improve the Clinical Management of Liver Cancer (T12-716/22R) led by SKLLR director, Professor Irene Ng.

During the day, Professor Feng and Professor Wang engaged in meetings and discussions with the Project Coordinator, Senior Researchers, Postdoctoral Fellows and RPG students of the project. They also paid a visit to the Centre for PanorOmic Sciences (CPOS) Lab to take a look and understand the research environment and equipment in HKU.

The full-day visit concluded with the seminar delivered by Professor Feng on "New Thoughts and Strategies of Liver Cancer Immunotherapy", which was open to all HKU staff and students and had led to interesting discussions among researchers.

The visit by Professor Feng and Professor Wang was a valuable learning experience for everyone involved. The advice and insights were greatly appreciated, and we look forward to the possibility of collaborating on future research projects.

Seminar Delivered by Professor Gen-Sheng Feng

Topic: Mechanistic Disection and Immunotherapy of Liver Cancer

Abstract: Despite the great success of immunotherapy in a broad range of cancers, even some life-saving miracles in a few patients at the advanced stages of melanoma or kidney tumor, the vast majority of cancer patients showed poor response or developed resistance to the immune checkpoint inhibitors (ICIs). Approximately 17% hepatocellular carcinoma (HCC) patients responded to monotherapy of pembrolizumab and 20% responded to nivolumab. A combination of nivolumab and ipilimumab increased the response rate to 30% in HCC. Simultaneous blockade of PD-L1 and VEGF signaling using atezolizumab and bevacizumab achieved better overall and progression-free survival than sorafenib in HCC (IMbrave 150). As a major organ of metabolism and detoxification, liver develops an intricate immunotolerant environment, which may restrict the effectiveness of immunotherapy.

Our previous data showed that monotherapy with anti-PD-L1 antibody (PD-L1) exhibited no inhibitory effect in primary liver cancer driven by classical oncogenes in mice. Given a robust induction of PD-L1 expression by polyinosinic:polycytidylic acid (polyIC) in the liver, we reasoned that the synthetic dsRNA could sensitize hepatic response to αPD-L1 treatment. Indeed, combined treatment of polyIC and αPD-L1 showed markedly improved efficacy in mouse HCC models. PolyIC is a TLR3 ligand that stimulates production of interferons and other cytokines, and has been used as an immune adjuvant.

We compared the efficacy of these reagents between subcutaneous and metastasized liver tumors derived from the same CRC cells, to identify liver-specific factors responsible for the poor response to immunotherapy. Despite potent suppression on tumor growth under the skin, αPD-L1 alone had no effect on the liver-grafted tumor progression. A combinatorial therapy of αPD-L1 and polyIC exhibited additive effect in subcutaneous tumors but an intriguing synergistic effect in liver tumors. We interrogated the compositions and changes of immune cell subtypes infiltrated into the tumors grown subcutaneously or in the liver, as well as the whole liver of tumor-bearing mice. This comparative analysis provides a fresh view on the unique immune ecosystem of liver tumors, and also prompts us propose a new thought on how to design effective liver cancer immunotherapy.