Invited talk 4
Dr. Carmen WONG
Department of Pathology, University of Hong Kong
Dr. Carmen Wong is currently an Associate Professor and Principal Investigator in the Department of Pathology and State Key Laboratory of Liver Research at the University of Hong Kong. She is the program leader of the liver cancer program at Center of Oncology and Immunology at InnoHealth, Hong Kong.
She obtained her PhD degree in the University of Hong Kong and completed her post-doctoral training in the Johns Hopkins University, studying the roles and molecular mechanisms of hypoxia (oxygen deprivation) in cancer metastasis.
Her research team currently focuses on the immune microenvironment in liver cancer. Over the years, her work was published in PNAS, Gastroenterology, Journal of Hepatology, GUT, Hepatology, Nature Communications, Cell Reports, and the Journal of Clinical Investigation.
She is the recipient of the Croucher Innovation Award, Outstanding Young Researcher Award of HKU, National Natural Science Foundation of China Excellent Young Scientist Fund, Hong Kong Young Scientist Award, the Best PhD thesis Awards of HKU, Croucher Fellowship, University of British Columbia (Canada) Alumni Builder Award. She is an elected member of the Hong Kong Young Academy of Science. She is the co-editor-in-chief of Hepatology Communications (AASLD).
Topic: Approaching personalized medicine with precision mouse liver cancer models
Summary: Hepatocellular carcinoma (HCC) is a lethal cancer which lacks effective treatments. Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) are the mainstay treatments for advanced HCC patients. TKIs have marginal survival benefits while ICIs are only effective in 20% of HCC patients. Identification of potential responders and non-responders of ICIs is pivotal to effective treatments. Meanwhile, the underlying mechanisms of ICI resistance and novel treatments to overcome the resistance are yet to be explored. Using somatic genome editing systems, we established a panel of precision mouse HCC models that resemble human HCCs with different driver mutations. This enables us to unravel the relationship of genetic and immune landscapes. Single cell transcriptomic sequencing and immunophenotyping revealed that the genetic composition of the HCC directly affected CD8+ T cell infiltration and activity, thereby determining the tumors’ response for anti-PD-1. Specific genetic alterations resulted in the formation of hot (abundant tumor-infiltrated CD8+ T cells) and cold (few tumor-infiltrated CD8+ T cells) tumors. We showed that hot tumors were responsive to single ICI treatment while cold tumors were only responsive for combined ICI and TKI treatment. Further, mass cytometry-based analysis of the tumor-infiltrated T cells in cold HCC revealed that T cells expressed higher level of inhibitory receptor, TIGIT, which interacted with its ligand PVR/PVRL1 expressed on HCC cells, keeping T cells inactive after PD-1 blockade. Anti-TIGIT improved the efficiency of anti-PD-1 in suppressing HCC. Moreover, we evaluated two first-in-class drugs, CFI-400945 and CFI-402257, PLK4 and TTK inhibitors as HCC treatments. These drugs not only perturbed cell cycle but unexpectedly induced cytosolic DNA accumulation, micronuclei formation, and DNA damage which together activated the STING pathway to drive the IRF3/7- and NFKβ-mediated transcription program of senescence-associated secretory phenotypes (SASPs) that led to immune cell infiltration in HCC. PLK4 or TTK inhibitor substantially extended the survival of mice with cold HCC and demonstrated durable anti-tumor effects when used in combination with anti-PD-1. Taken together, our work paves the way to personalized medicine for different but the most effective treatment modalities involving ICIs.