Abstract P59: Targeting TGF-β signaling pathway to reverse immune checkpoint blockade resistance in hepatocellular carcinoma

Abstract

Immune checkpoint blockade (ICB) therapies have reshaped the treatment paradigm across various cancer types. In hepatocellular carcinoma (HCC), the combination of anti-PD-L1 and anti-VEGF, approved as new first-line treatment, has shown improved overall survival. However, response rate remains modest, driving the development of immunotherapy-based combination strategies. Our in-house clinical single cell RNAseq data revealed that transforming growth factor-beta (TGF-β) expression was widespread across multiple cell types in the tumor microenvironment (TME) and up-regulated in non-responders. Furthermore, TREM2+ macrophages were identified as the top predicted receiver, and their abundance was also increased in non-responders. Based on these findings, we administered Vactosertib, a TGF-β receptor (TGFBR1) inhibitor, combined with anti-PD-1, in our HCC resistant mouse model. This combination effectively overcame ICB resistance and significantly reduced TREM2+ macrophages. These findings confirm the important role of TGF-β in driving ICB resistance, potentially through TREM2+ macrophages that promote an immunosuppressive TME. Future studies will focus on uncovering how TGF-β modulates TREM2+ macrophages to support immune evasion and therapeutic resistance. Targeting this axis may offer an effective strategy to overcome resistance and improve the clinical efficacy of immunotherapy in HCC. Our long-term goal is to understand how TGF-β influences the phenotype and function of macrophages, leading to a new design of novel combination treatments that can enhance anti-tumor immunity and improve responses to immune checkpoint blockade.