Postdoctoral Fellow The University of Hong Kong, Hong Kong
Abstract: Despite the increasing use of immune-checkpoint blockade (ICB) as standard care in hepatocellular carcinoma (HCC), the multifaceted heterogeneity of HCC and its diverse immune microenvironment remain major challenges to the efficacy of ICB, with the treatment benefiting only a minority of HCC patients. CTNNB1 mutations, the most common driver mutations in HCC, play a crucial role in regulating cancer cell plasticity, tumor progression, and drug resistance. Recent findings have also highlighted the link between CTNNB1 and T cell exclusion and as a consequence poor ICB response. Our current analysis of public human HCC patient data unveiled distinct immune profiles between CTNNB1-mutated and non-CTNNB1-mutated patients. Through comparing clinically relevant murine models of CTNNB1-mutated and non-CTNNB1-mutated HCC, we observed that CTNNB1-mutated tumors exhibit enhanced β-catenin activation, reduced CD8+ T cell infiltration, and their compromised mobility and proliferation capabilities as compared to non-CTNNB1-mutated tumors. scRNA-seq analysis of these mouse tumors also demonstrated a decrease in effector CD8+ T cells and an increase in monocyte population in CTNNB1 mutation-driven HCCs. Notably, these enriched monocytes expressed signatures of classical monocytes and displayed elevated levels of THBS1 in CTNNB1-mutated HCC, showcasing immunosuppressive characteristics. The enrichment of monocytes was likewise consistently observed in CTNNB1-mutated HCC patients. A high THBS1+ monocytic myeloid-derived suppressor cell (mMDSC) signature not only predicted poor survival and correlated positively with advanced tumor stages but also indicated a poor response to ICB in CTNNB1-mutated HCC patients. In summary, the presence of THBS1+ monocyte-like cells emerges as a promising predictive marker for immunotherapy response in CTNNB1-mutated HCC patients, offering valuable insights for future therapeutic strategies.
Funding Source: RGC Research Fellow Scheme RGC Research Impact Fund (R7022-20) RGC Theme-Based Research Scheme (T12-705-24-R)
