Abstract Immuno-oncology has revolutionized cancer treatment by harnessing the immune system to target and eliminate tumors. However, developing effective therapies remains challenging due to the complexity of the tumor microenvironment (TME), which significantly influences tumor development, progression, and the response to therapies1. Traditional preclinical models have provided valuable insights but fail to fully replicate the dynamic interactions within the human TME. Animal models often do not recapitulate human-specific immune responses, and 2D models lack tissue architecture, limiting their ability to study TME complexities, like immune cell trafficking and tumor immune evasion2. These limitations highlight the need for more accurate, human-relevant tumor models2-3. To address these challenges, we have developed a 3D vascularized tumor-on-a-chip model that contains essential TME features to enhance clinical relevance. By leveraging 3D bioprinting technologies, we integrate complex vascular architectures with our human vascularized integrated organ system (h-VIOS™), enabling dynamic vascular perfusion for up to 21 days and simulating the flow of circulating cells. The vasculature is endothelialized with primary human umbilical vein endothelial cells (HUVECs) to form a functional barrier that expresses junctional markers (e.g., ZO-1) and adhesion molecules (e.g., ICAM-1), enabling endothelial-immune cell interactions during T cell trafficking and tumor infiltration. Our tumor-on-a-chip platform integrates patient-derived tumor organoids (PDOs), which reproduce critical tumor characteristics, including heterogeneity, genetic diversity, and growth kinetics. By co-culturing endothelial cells, immune cells and tumor organoids, our model simulates intrinsic properties and interactions of the TME. In a colorectal cancer (CRC) model, we demonstrated enhanced chemokine-driven T cell infiltration from the endothelialized vasculature into the tumor compartment, as confirmed by confocal imaging and flow cytometry. Furthermore, we modeled T cell responses to immune checkpoint inhibition with pembrolizumab. The experimental results showed enhanced T cell-induced tumor killing, evidenced by increased levels of markers such as IFN-γ, Granzyme B, and cleaved-caspase 3, as compared to the control conditions. These findings provide proof-of-concept for anti-PD-1 efficacy in our model, suggesting that it effectively captures T cell reactivation and tumor killing in response to immunotherapy. In conclusion, our 3D vascularized tumor-on-a-chip model offers advantages over traditional models by more closely mimicking the TME. This customizable model not only enables the study of immune cell recruitment, migration, and tumor-cell killing in response to immunotherapies but also holds great potential for personalized medicine, providing a powerful tool for advancing immuno-oncology research and improving therapeutic outcomes. Citation Format: Juliana Navarro Yepes, Queeny Dasgupta, Purboja Purkayastha, Carly Truong, YongDuk Han, Michael Doerfert, Cassio Mello, Kevin Janson, Ameya Narkar, Sammy Datwani, SoonSeng Ng, Taci Pereira. Bioprinted Vascularized Tumor-on-a-Chip model for Immuno-Oncology therapeutic development: Recapitulating the Tumor Microenvironment and Immune cell dynamics [abstract]. In: Proceedings of the AACR IO Conference: Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2025 Feb 23-26; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2025;13(2 Suppl):Abstract nr B114.
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Mar 12, 2025
Lei Cui 
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