Abstract 2514: Pancreatic cancer subtype-specific secreted factors determine the immunosuppressive tumor microenvironment

Pancreatic ductal adenocarcinoma (PDAC) is a complex disease displaying genetic heterogeneity along with a tumor microenvironment (TME) unique in its composition. Whereas the PDAC TME is known to be highly immunosuppressive, it remains elusive how distinct genetic alterations affect TME cell type recruitment and how this, in turn, influences progression and treatment outcome. Therefore, we systematically investigated the TME composition and tumor-immune crosstalk in molecular PDAC subtypes. We delineated the TME landscape of a comprehensive tumor cohort derived from Kras-driven PDAC mouse models by integrating single cell RNA-sequencing (scRNA-seq) with histopathological analysis, tissue RNA-seq followed by deconvolution and flow cytometry immunophenotyping. Our results show that distinct molecular PDAC subtypes recruit divergent subpopulations of infiltrating immune cells, most notably evidenced by major differences in frequency and phenotype of macrophages and neutrophils. Functional secretome analysis of well-characterized Kras-driven mouse and primary human PDAC cell lines revealed subtype-specific factors which differ between the two main transcriptional subtypes of PDAC (classical and mesenchymal). Accordingly, crosstalk between tumor and immune cells inferred by interaction probability analysis through ligand-receptor pairs from scRNA-seq data nominates the CSF signaling network as a key player in mesenchymal PDAC, whereas CXCL signal hubs mediate higher infiltration of immunosuppressive neutrophils in classical tumors. Our findings contribute to the understanding of PDAC subtype-specific biology and aid the identification of potential immunotherapeutic vulnerabilities thereof. Citation Format: Stefanie Bärthel, Chiara Falcomatà, Sebastian A. Widholz, Albulena Toska, Fabio Boniolo, Constantin Schmitt, Vanessa Gölling, Jonathan Swietlik, Jonas Mir, Moritz Jesinghaus, Felix Meissner, Roland Rad, Marc Schmidt-Supprian, Dieter Saur. Pancreatic cancer subtype-specific secreted factors determine the immunosuppressive tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2514.