Disrupting macrophage metabolism to reduce immunosuppression and enhance therapy in pancreatic cancer

Abstract public domain (NIH RePORTER)

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDA) has the worst five-year survival rate of any major cancer. The lethality of PDA is largely due to a lack of effective treatment options. Several barriers in PDA treatment are conferred by the presence of immunosuppressive myeloid cells, which are highly represented in these tumors. This immune suppression, driven largely by myeloid cells, renders PDA refractory to immunotherapy which has proven effective in other solid tumors. Consequently, the elimination or reprogramming of these myeloid cells offers potential avenues to provide a much-needed breakthrough for the treatment of patients with PDA. The working hypothesis of this supplemental research proposal is that interruption of the metabolic mechanisms driving immune suppression will enable T cell killing of PDA cells. This will be examined in two parts. First, a live cell imaging assay will be developed to assess the requirement of metabolic mechanisms of immune suppression on the ability of T cells to kill PDA cells in a spatial and temporal manner (Aim 1). Next, the contribution of proline produced through macrophage catabolism of arginine to collagen produced by fibroblasts will be measured through a series of assays (Aim 2). Collectively, these data will strengthen the results from Aim 2 of the parent grant, and promote the diversity of the cancer research community.

Public health relevance public domain (NIH RePORTER)

Project Narrative Pancreatic cancer is a deadly disease which currently has no clinically effective treatment options. While promising in other cancers, immunotherapy has thus far proven ineffective in pancreatic cancer. The goal of this project is to directly test immunosuppression mediated by metabolic pathways in myeloid cells and T cell killing of PDA cells.