Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Cell Metab. 2019 Jun 4;29(6):1390-1399.e6. doi: 10.1016/j.cmet.2019.02.001. Epub 2019 Feb 28.

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by abundant infiltration of tumor-associated macrophages (TAMs). TAMs have been reported to drive resistance to gemcitabine, a frontline chemotherapy in PDA, though the mechanism of this resistance remains unclear. Profiling metabolite exchange, we demonstrate that 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. Together, these findings provide insights into the role of macrophages in pancreatic cancer therapy and have potential to inform the design of future treatments. Additionally, we report that pyrimidine release is a general function of alternatively activated macrophage cells, suggesting an unknown physiological role of pyrimidine exchange by immune cells.

Keywords: deoxycytidine; gemcitabine resistance; immunometabolism; macrophage; metabolic crosstalk; metabolomics; pancreatic cancer; pancreatic ductal adenocarcinoma; tumor microenvironment; tumor-associated macrophage.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Pancreatic Ductal / drug therapy*
  • Carcinoma, Pancreatic Ductal / metabolism
  • Carcinoma, Pancreatic Ductal / pathology
  • Cells, Cultured
  • Deoxycytidine / analogs & derivatives*
  • Deoxycytidine / therapeutic use
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Pancreatic Neoplasms / drug therapy*
  • Pancreatic Neoplasms / metabolism
  • Pancreatic Neoplasms / pathology
  • Pyrimidines / metabolism*
  • Pyrimidines / pharmacology*
  • RAW 264.7 Cells
  • Xenograft Model Antitumor Assays

Substances

  • Pyrimidines
  • Deoxycytidine
  • gemcitabine