Dr. LEI Mang Leng, a PhD graduate in the Department of ABCT, won the prestigious PolyU PhD Thesis Award - Outstanding Award 2024

Thesis Title: Identification of Wild-Type Kirsten Rat Sarcoma (Kras) and its Signalling Pathway in Immune Evasion in Hepatocellular Carcinoma

- For contribution to enhance the therapeutic efficacy of current immunotherapy in liver cancer

Chief Supervisor: Professor Terence LEE

Although immunotherapy demonstrate tremendous promise for the treatment of hepatocellular carcinoma (HCC) patients, their response rates are modest (~15%). Increasing evidence indicates that activation of oncogenic pathways contributes to an unfavourable tumour microenvironment, resulting in resistance to immunotherapy. Using an antigen-expressing c-MycOE /Tp53KO HCC mouse model, DIA-MS proteomics identified oncogenic KRAS signalling pathway as a crucial mediator of immune evasion and confers resistance to anti-PD-1 therapy. Wild-type KRAS was highly upregulated in immune-escaped tumours, with concurrent activation of EGFR/MEK/ERK signalling. Endogenous Kras overexpression increased tumour burden and reduced survival in mice. KRAS exerted inhibitory effects on both intrinsic and extrinsic interferon (IFN) responses, leading to the downregulation of MHC-I expression and dampened CD8+ T cell activity. Notably, combination therapy with MRTX0902, trametinib, and anti-PD-1 antibody effectively increased intratumoural CD8+ T cell infiltration and improved survival. This study provided new insights into the therapeutic potential of targeting the wild-type KRAS pathway to increase the efficacy of anti-PD-1 therapy in HCC.