Abstract B042: A micro-vascularized organ-on-chip model of PDAC reveals immune exclusion and altered macrophage polarization

Abstract Pancreatic ductal adenocarcinoma (PDAC) exhibits profound immune evasion capabilities by remodeling the tumor microenvironment (TME) into an anti-inflammatory, immunosuppressive niche. This includes the establishment of chemokine gradients and physical barriers that restrict the recruitment and infiltration of immune effector cells. To investigate these interactions in a physiologically relevant context, we leveraged our recently published PDAC-on-chip model (Deipenbrock et al., 2025) for further matrix integration and direct vascularization. To this end, we employed Dynamic42 two- and three-channel biochips to model immune cell migration from the vasculature into PDAC tumor structures. PDAC co-spheroids, comprising primary cancer-associated fibroblasts (CAFs) and Panc1 tumor cells, were embedded in an extracellular matrix within a dedicated channel of the chip. Over a 10-day period, fibroblasts formed a fibrotic barrier exceeding 100 µm in thickness around the tumor core. Additionally, endothelial cells incorporated into the matrix developed a perfusable microvascular network that directly interfaced with the TME. Various immune cell populations were then introduced into the vascular channel, and their transmigration across a porous membrane into the complex TME was monitored over time using live-cell imaging and flow cytometry. Our results demonstrate that PDAC-on-chip models effectively inhibit T cell infiltration, supporting the notion of active immune exclusion by the tumor. Furthermore, myeloid cells were skewed toward an M2-like phenotype within the TME, as evidenced by the upregulation of CD163 and CD206 on infiltrating tumor-associated macrophages. These findings underscore the critical role of tumor-stroma composition in modulating immune cell recruitment, activation, and polarization. The described microvascularized PDAC-on-chip model faithfully recapitulates key aspects of PDAC immune evasion observed in vivo and offers a promising platform for testing immunotherapeutic strategies in a controlled microphysiological environment. Deipenbrock, A. et al. (2025) ‘Modelling of the multicellular tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on a fit-for-purpose biochip for preclinical drug discovery’, Lab Chip, p. Available at: https://doi.org/10.1039/D4LC01016G. Citation Format: Thomas Sommermann, Amélie Paillereau, Alina Deipenbrock, Martin Raasch, Nicole Teusch, Knut Rennert. A micro-vascularized organ-on-chip model of PDAC reveals immune exclusion and altered macrophage polarization [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B042.