Background
Innovative immunotherapy drugs such as immune checkpoint inhibitors (ICIs) have replaced the first-line treatment for many cancers, however, their therapeutic effects on primary and secondary liver cancers are limited. Clinician researchers including myself have noticed that unwanted locoregional inflammation may lead to disease progression and therapy resistance in the liver. My research has identified a group of liver “inflammation checkpoints” that can diminish cancer-promoting inflammation and enhance anti-tumour immunity. I have also developed liver inflammation-targeted strategies to improve immunotherapy efficacy and resolve conventional therapy resistance. This project will take advantage of my years of clinical expertise in ICI resistance and my research experience in cancer-promoting inflammation, emphasising how CD8 T cells are regulated by ICI-induced liver-specific inflammation.
Aim
This project aims to investigate the post-ICI CD8 T cell trajectory in the liver and understand how intrahepatic inflammatory signals impose on T cell function. By identifying and leveraging new immune populations and molecular targets, we intend to design relevant combination strategies to orchestrate anti-tumour immunity in the liver.
Approach
Based on genetically modified mice and clinical samples, we will investigate the post-treatment cancer microenvironment using single-cell sequencing and multiplex immunohistochemistry. Different mouse strains will be used for tumour inoculation and drug administration. Mouse or human tissues will also be acquired for in vitro culture systems. In addition to high-throughput flow cytometry and other immunological analyses, molecular & cellular biology experiments and multi-omics methods will be applied to mechanistic exploration.
Project Potential
This project will reveal a phase-and-context-dependent regulation of CD8 T cell anti-tumour immunity, potentially breaking the liver-specific barriers to immunotherapy response.