Abstract C069: Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is overwhelmingly resistant to therapy. PDAC tumors are characterized by an immunosuppressive fibroinflammatory stroma and can be broadly classified into those with an abundance of T cells or a paucity of T cells. Our lab has previously identified several tumor cell intrinsic factors that regulate the degree of T cell infiltration and response to immunotherapy, but it remains unknown how these factors influence T cell trafficking through the vasculature to the tumor. We used in vivo models and a cancer-on-a-chip platform to examine immune-vascular crosstalk in the pancreatic tumor microenvironment (TME). We first sought to characterize the vascular landscape in PDAC. Following up from previous work in the lab, we used bulk RNA sequencing appraoches to identify a subset of hyper-vascular murine PDAC lines. Using an in vivo dextran assay, we determined that endothelial-high tumors have increased vascular perfusion. We next utilized an in vitro tube formation assay to assess if the defects seen in tumor vasculature are from tumor-cell derived factors. Endothelial cells cultured in conditioned media from endothelial-low tumors had defects in tubule formation. We further identified endothelial-low tumors have a defect in pericyte coverage of the vessel. We next utilized organ-on-a-chip devices to assess angiogenesis in PDAC. Endothelial cells and fibroblasts self-assemble into a 3D vascular network when incorporated into the microdevices. In the absence of tumor cells, mature vascular networks formed on day 4 of culture. Interestingly, vascular networks formed faster in the presence of PDAC tumor cells, suggesting a tumor derived factor enhanced angiogenesis. The cancer-on-a-chip devices are perfusable and allow for the incorporation of other TME components. Future directions, include incorporation of myeloid cells and perfusing fluorescently labeled T cells into the vascular networks and using live imaging to monitor T cell trafficking in different PDAC TME settings. Further, we will use immune checkpoint blockade and CAR T cells to identify methods to enhance tumoral T cell infiltration. Citation Format: Samantha B. Kemp, Andrei Georgescu, Jason Pitarresi, Takeshi Katsuda, Il-Kyu Kim, Dora Racca, John Tobias, Dan Huh, Ben Stanger. Using a cancer-on-a-chip approach to study the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C069.