Nov 5, 2018

Macrophage Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

BioRxiv : the Preprint Server for Biology
Christopher J HalbrookCostas A Lyssiotis

Abstract

Pancreatic Ductal Adenocarcinoma (PDA) is characterized by abundant infiltration of tumor associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, the front-line chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate macrophages programmed by PDA cells release a spectrum of pyrimidine species. These include deoxycytidine, which inhibits gemcitabine through molecular competition at the level of drug uptake and metabolism. Accordingly, genetic or pharmacological depletion of TAMs in murine models of PDA sensitizes these tumors to gemcitabine. Consistent with this, patients with low macrophage burden demonstrate superior response to gemcitabine treatment. Additionally, we report pyrimidine release is a general function of anti-inflammatory myeloid cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

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Mentioned in this Paper

Metabolic Process, Cellular
Immune Effector Cell
Pancreatic Ductal Adenocarcinoma
Pancreatic Carcinoma
Murine
Anti-Inflammatory Agents
Uptake
Neoplasms
Malignant Neoplasm of Pancreas
Myeloid Cells

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