Project 3: Impact of tumor genetics on PDAC immunobiology and responses to macrophage-targeted immunotherapy

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ABSTRACT (Project 3) Pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy that is poorly responsive to treatment, is characterized by a prominent infiltration of immune cells. In particular, macrophages are abundant within the tumor microenvironment (TME) in PDAC and contribute to disease progression and treatment resistance. However, the factors affecting the recruitment and distribution of immune cells, including macrophages, in PDAC remain largely unknown. Recently, our collaborators in Project 1 found that tumors differing in their Trp53 status exhibited different immune profiles. Our collaborators further observed that the cell type of origin (acinar or ductal) influenced the tumor molecular subtype (classical or basal-like), which is also known to be shaped by the immune composition of the tumor. We postulate that somatic alterations in cancer cells, the cell type of origin, and tumor molecular subtype influence the immune landscape within the TME and throughout the host during PDAC progression. To test this hypothesis, we will determine immune cell frequency, distribution, and function in the TME and throughout the host using high-dimensional analytical tools (CODEX and CyTOF) on genetically engineered mouse models (GEMMs) of PDAC that vary in their driver mutations and cell type of origin (developed by Project 1). Additionally, we will use molecular methods to identify immunomodulatory factors regulating immune cell recruitment in the context of different genetic mutations and cell type of origin, and we will use genetic, pharmacological, and neutralizing antibody-based approaches to confirm the functional effects of these factors in driving PDAC progression. Importantly, we will validate findings from these studies in human PDAC specimens and in cell lines derived from human pancreatic ductal cells. Finally, we recently found that the pattern recognition receptor, Dectin-2, is expressed on tumor- associated macrophages (TAMs) in an aggressive, transplantable model of PDAC. Notably, administration of natural Dectin-2 ligands induces sustained PDAC regression in a T-cell dependent manner by reprogramming immunosuppressive TAMs into immunostimulatory antigen-presenting cells (APCs). We hypothesize that PDAC can be effectively treated by reprogramming Dectin-2+ TAMs into immunostimulatory APCs. We will treat autochthonous tumors arising in the GEMMs developed by Project 1 with Dectin-2 ligands to test this hypothesis. Furthermore, to identify mechanisms by which Dectin-2 stimulation is therapeutically efficacious, we will use CODEX and CyTOF to observe changes to the immune landscape occurring within the TME and throughout the host upon treatment. Molecular approaches will be used to identify immunomodulatory factors responsible for mediating therapeutic efficacy. Together, these studies will improve our understanding of how the immune system is altered during PDAC development in the context of variation in genetic mutations, cell type of origin, and molecular subtype, and in response to TAM reprogramming.