Stomal Senescence Regulator of Tumor Immunity and Progression

Project Summary The 5-year survival rate for patients diagnosed with pancreatic ductal adenocarcinomas (PDACs) is 11%. This poor outcome is due to multiple factors, including rapid progression to metastatic disease, poor clinical responses to standard of care therapies, and no effective targeted or immunotherapeutic approaches1. The treatment refractory nature of PDAC is likely due in part to the profoundly fibrotic and immune suppressive tumor microenvironment (TME) that is a hallmark of this disease. Two major drivers of this TME include a dense fibrotic tumor stroma and a robust infiltration of tumor-supportive myeloid cells. PDAC contains phenotypically diverse cancer associated fibroblasts (CAFs) subsets. These subsets include myofibroblasts (myCAF), inflammatory fibroblasts and a small subset of antigen presenting CAFs. Recently, it has been proposed by some investigators that myCAFs may have tumor restraining properties, while other investigators have found myCAFs can promote tumor progression and treatment resistance. What is clear is that tumor restraining or tumor promoting features are likely phenotype and context dependent. We propose herein that cellular senescence may be distinguished by the tumor-promoting and restraining CAF subsets. Our overall hypothesis that: Stromal senescence plays a key role in driving tumor progression by altering tumor immune and ECM properties. To address this hypothesis, we will use state of the art biophysical and immunological techniques in human PDAC specimens, and state of the art genetically engineered mouse models for both PDAC and the study of senescent cells, to evaluate the following aims. Aim 1. Determine how biophysical properties of the extracellular matrix regulate the induction and function of senescent CAFs. Aim 2. Determine the impact of senescent CAFs on myeloid and dendritic cell driven immune surveillance. Aim 3. Determine the organ specific impact of senescent CAFs on metastatic progression. Significance: Understanding how the PDAC TME's regulate tumor immunity is critical to employing stromal modulatory therapy to enhance immunotherapeutics. This concept is central to these studies.