Abstract A25: Using biomaterial scaffolds to study the genesis of the immunosuppressive premetastatic niche in pancreatic cancer

Abstract

Abstract Pancreatic cancer is a lethal malignancy with a 5-year survival rate of less than 10%. This poor prognosis is, in part, due to patients most often presenting with already metastatic disease. Pancreatic cancer is characterized by an abundant, reactive fibroinflammatory stroma, consisting of cancer-associated fibroblasts (CAFs) and infiltrating immune cells that send and receive signals to and from other nearby cells, including the tumor cells. The crosstalk between tumor cells and elements of the stroma results in an immunosuppressive tumor microenvironment both at the primary tumor and the sites of metastases. A key limitation in studying metastatic disease in mouse models is the inability to predict when the cancer cells will ultimately metastasize. In this study biomaterial scaffolds that mimic the premetastatic niche in vivo, by attracting immune cells followed by tumor cells, were used to longitudinally follow the metastasis process in individual animals. Biomaterial scaffolds were implanted subcutaneously to mimic the premetastatic niche in both syngeneic and spontaneous mouse (iKras* p53*) models of pancreatic cancer. Scaffolds were harvested 21 days post implantation and taken for histologic analysis to characterize the cellular infiltrate in response to the primary tumor. Histologic analysis (H&E, Gomori’s trichrome, and multiplex IHC) shows tumor cell colonization in the scaffold along with a robust immune and fibrotic response. To further characterize the scaffold infiltrate in control versus tumor-bearing mice, mass cytometry (CyTOF) and single-cell RNA sequencing (scRNA seq) analysis was performed. CyTOF analysis revealed the most abundant cell population is heterogenous myeloid cells, which are immunosuppressive in nature. Scaffolds from tumor-bearing animals have an increase in fibroblasts, and subsequently have fewer cytotoxic, CD8+ T cells. scRNA seq analysis of the scaffold infiltrate reveals CD8+ T cells from tumor-bearing animals express higher levels of the immune checkpoint, programmed cell death protein 1 (PD-1) and lower levels of the functional markers, perforin 1 and granzyme B, suggesting the CD8+ T cells are unable to perform their cytotoxic functions. Further analysis revealed a chemokine signaling axis, where fibroblasts recruit distinct subsets of myeloid cells. Taken together, the premetastatic niche (recapitulated by the biomaterial scaffolds) in pancreatic cancer has a high abundance of immunosuppressive myeloid cells, an increase in fibroblasts, and fewer CD8+ T cells, creating an immunosuppressive niche that allows for tumor cell colonization and growth. Future directions include blocking myeloid cell chemotaxis to the scaffold to prevent tumor cell dissemination and reduce metastatic burden. Citation Format: Samantha Kemp, Nina Steele, Eileen Carpenter, Veerin Sirihorachai, Grace Bushnell, Aaron Morris, Carlos Espinoza, Fatima Lima, Zeribe Nwosu, Sophia Orbach, Lonnie Shea, Filip Bednar, Howard Crawford, Marina Pasca di Magliano. Using biomaterial scaffolds to study the genesis of the immunosuppressive premetastatic niche in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A25.