Abstract PR13: Macrophage metabolism inhibits pancreatic cancer therapy

Pancreatic ductal adenocarcinoma (PDA) is projected to become the 3rd most prevalent cancer-related death in the United States in 2016, contrasting a relatively low incidence rate. The lethality of PDA is largely due to a lack of effective treatment options. A principal barrier in PDA treatment is the physiology of the tumors, characterized by a densely fibrotic stroma, rich with immune cell infiltration. The majority of these immune cells are immunosuppressive myeloid cells, including macrophages. These macrophages within the tumor, termed tumor-associated macrophages (TAMs), are strongly immunosuppressive, inhibiting both infiltration and activation of cytotoxic T cells. While immunotherapy has emerged as a promising strategy to treat other solid tumors, immune suppression has rendered PDA refractory to such approaches. Accordingly, much effort has been made to understand the role of TAMs in pancreatic tumorigenesis and tumor maintenance. Several studies have identified pathways by which PDA cells recruit and polarize macrophages into TAMs and the effects that TAMs have on the tumor microenvironment. Depletion of TAMs leads to the inhibition or regression of tumor growth, mediated largely by increased infiltration of cytotoxic T cells into the tumor. In addition to signaling proteins, metabolic byproducts can also influence cellular crosstalk in the tumor microenvironment; however, this has not been described in the context of PDA. Utilizing reciprocal conditioned media approaches combined with LC/MS metabolomics, we have profiled the metabolic crosstalk between cancer cells and macrophage cultures and found TAMs release metabolites that can regulate the response of PDA cells to chemotherapy. We further noted several additional metabolic pathways by which TAMs can deplete important nutrients in the microenvironment to directly inhibit T-cell activity. Taken together, these data provide mechanistic insight into previous reports that macrophages can drive immune and chemoresistance in PDA. Furthermore, these results also suggest that further development of interventions that target either PDA-mediated polarization of TAMs or TAM-mediated inhibition of therapy represent opportunities to improve the efficacy of currently available treatment options. This abstract is also being presented as Poster A36. Citation Format: Christopher J. Halbrook, Rosa Menjivar, Galloway Thurston, Marina Pasca di Magliano, Costas Lyssiotis. Macrophage metabolism inhibits pancreatic cancer therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr PR13.