In vitro integration of a functional vasculature to model endothelial regulation of chemotherapy and T-cell immunotherapy in liver cancer
Jyothsna Vasudevan, Ragavi Vijayakumar, Jose Antonio Reales‐Calderón, Maxine Lam, Jin Rong Ow, Joey Aw, Damien Tan, Anthony T. Tan, Antonio Bertoletti, Giulia Adriani, Andrea Pavesi
Abstract
The complex tumor microenvironment (TME) presents significant challenges to the development of effective therapies against solid tumors, highlighting the need for advanced in vitro models that better recapitulate TME biology. To address this, we developed a vascularized human liver tumor model using a microfluidic platform, designed to test both drug and cell-based therapies. This model mimics critical tumorigenic features such as hypoxia, extracellular matrix (ECM), and perfusable vascular networks. Intravascular administration of Sorafenib demonstrated its ability to disrupt vascular structures significantly, while eliciting heterogeneous responses in two distinct liver tumor cell lines, HepG2 and Hep3b. Furthermore, treatment with engineered T-cells revealed that the tumor vasculature impeded T-cell infiltration into the tumor core but preserved their cytotoxic capacity, albeit with reduced exhaustion levels. Cytokine analysis and spatial profiling of vascularized tumor samples identified proinflammatory factors that may enhance T-cell-mediated antitumor responses. By capturing key TME characteristics, this microfluidic platform provides a powerful tool enabling detailed investigation of tumor-immune and tumor-vascular interactions. Its versatility could serve as a promising bridge between preclinical studies and clinical testing, offering opportunities for developing and optimizing personalized therapeutic strategies for solid tumors. • Developed an in vitro model of a human liver tumor integrated with a functional vasculature within a microfluidic platform. • Sorafenib disrupted tumor vasculature and induced heterogenous responses in different liver tumor subtypes. • Tumor vasculature reduced the infiltration of engineered T-cells but preserved its cytotoxic capacity. • Spatial profiling of the tumor microenvironment revealed activation and exhaustion patterns in engineered T-cells.