Combination CAF/myeloid targeting for pancreatic cancer therapy

Pancreatic ductal adenocarcinoma (PDA) is projected to become the second leading cause of cancer-related death by 2030. The high mortality of PDA is due in large part to its extreme resistance to chemotherapy. Recent efforts to harness the immune system to attack PDA using either vaccines or checkpoint blockade inhibitors have also been unsuccessful due to local immunosuppression mediated by the tumor stroma. The stroma comprises up to 90% of the volume of pancreatic tumors and harbors multiple immunosuppressive cell types. Both cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs) have immunosuppressive functions, linking stromal composition to decreased invasion of cytotoxic T cells. As stromal growth is controlled by epithelial tumor cells in paracrine signaling cascades, the exposition of such mechanisms is an important goal for immune targeting of PDA.Preliminary work from our group has demonstrated that CAFs and MDSCs cooperate in the suppression of cytotoxic T cells. Therefore, we hypothesize that combined targeting of both CAFs and MDSCs in pancreatic tumors will relieve local immunosuppression, thus favoring the influx of cytotoxic T cells. However, effectively modulating the intricate interplay of stroma cells requires a detailed understanding of the nature of the paracrine signals that regulate stromal interaction. In this project, we will determine the mechanisms by which CAFs and MDSCs cooperate to suppress cytotoxic T cells in PDA and employ therapeutic approaches to reverse this immunosuppression in an advanced genetically engineered mouse model. We will perform single cell RNA sequencing on matched pre-treatment biopsies and post-treatment necropsy samples from mice treated with agents targeted to MDSC and CAF populations, enabling a comprehensive characterization of the impacts of different agents on each cell type within an intact tumor setting. Mechanistic studies will be complemented with immune profiling, functional studies, and survival analysis. By comparing our in vivo findings to human PDA tissue explants, we will validate interdependencies of stromal cells revealed in murine PDA in the human context via immunofluorescence and RNA sequencing to allow conclusions about the applicability of our proposed therapeutic approach. By combined targeting of CAFs and MDSCs, we aim to reactivate the innate immune response to effectively target PDA. The long-term goal is to translate our in vivo findings to a novel immunotherapeutic strategy for stromal reprogramming in PDA patients. This is of pivotal clinical relevance to improve patient outcome by enhancing both the innate immune response and susceptibility for further chemotherapeutic approaches.