Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Christopher J. Halbrook, Corbin Pontious, Ilya Kovalenko, Laura Lapienyte, Stephan Dreyer, Ho Joon Lee, Galloway Thurston, Yaqing Zhang, Jenny Lazarus, Peter Sajjakulnukit, Hanna S. Hong, Daniel M. Kremer, Barbara S. Nelson, Samantha Kemp, Li Zhang, David Chang, Andrew Biankin, Jiaqi Shi, Timothy L. Frankel, Howard C. CrawfordJennifer P. Morton, Marina Pasca di Magliano, Costas A. Lyssiotis

Research output: Contribution to journalArticlepeer-review

256 Scopus citations

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. Macrophages are present in high abundance in pancreatic ductal adenocarcinoma. Halbrook et al. identify that alternatively activated macrophages release a spectrum of pyrimidine nucleosides that are consumed by pancreatic cancer cells. Among these, deoxycytidine can directly compete with gemcitabine, hindering its efficiency as a chemotherapy.

Original languageEnglish (US)
Pages (from-to)1390-1399.e6
JournalCell Metabolism
Volume29
Issue number6
DOIs
StatePublished - Jun 4 2019

All Science Journal Classification (ASJC) codes

  • Physiology
  • Molecular Biology
  • Cell Biology

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