Angiotensin System Inhibition in Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that is characterized by its rich stroma. Targeting the PDAC stroma holds great potential as a novel PDAC treatment regimen, as the tumor stromal microenvironment is significantly associated with patient overall survival. However, a means to safely and effectively normalize PDAC stroma is still being tested. For my dissertation, I explored the significance of the renin-angiotensin system (RAS), a hormonal system in PDAC progression, metastatic development and treatment. First, I examined the effects of long-term use of angiotensin system inhibitors (ASI) on the survival of patients with PDAC by retrospectively analyzing the Massachusetts General Hospital (MGH) patients’ records. I found that chronic ASI use was independently associated with longer overall survival in non-metastatic PDAC patients. Gene expression profiling using clinical samples suggested that the improved survival rate associated with ASI therapy might be due to the normalization of the extracellular matrix (ECM) and enhanced activity of immune cells. I then further characterized the stromal effect of angiotensin inhibition on PDAC using patient samples and murine models. In human tumors, ASI was associated with remodeling of ECM, normalization of angiotensin receptor positive stromal cells, and increased expression of normal stroma signature. In murine models, ASI normalized PDAC-associated fibroblasts by decreasing their ECM synthesis. Lastly, using murine models, we explored the potential of targeting RAS to enhance immunotherapy to prevent the onset of PDAC liver metastasis, which is the leading cause of PDAC related mortality. We found that in angiotensin receptor type 1a knockout (AT1KO) mice, the establishment of liver metastasis was delayed compared to wildtype (WT) mice. AT1KO also had fewer liver macrophages and splenic monocytes. Moreover, macrophages recruited to the disease-bearing liver and metastatic lesions expressed less macrophage type 2 (M2) markers and more macrophage type 1 (M1) markers respectively in AT1KO mice. With the reduction of immunosuppressive cells in the liver, immune checkpoint blockers significantly prolonged the survival of AT1KO mice compared to WT mice. In summary, chronic use of ASI is associated with longer overall survival in non-metastatic PDAC patients in retrospective analysis. Targeting angiotensin system in PDAC could potentially normalize the tumor microenvironment in human PDAC tumors and murine PDAC models. RAS inhibition may also enhance immunotherapy efficacy and prevent metastatic progression by re-engineering the immunosuppressive tumor microenvironment.