Macrophage-Derived Nucleosides Reduce the Efficacy of Gemcitabine

Pancreatic adenocarcinoma (PDAC) tumorigenesis is greatly influenced by an inflammatory response mediated significantly by immunosuppressive tumor-associated macrophages (TAM) in the tumor microenvironment (TME); conversely, the TME induces the metabolic reprogramming of TAMs. Recently, it has been shown that the presence of TAMs is associated with therapeutic response in patients with PDAC; thus, Halbrook and colleagues sought to ascertain whether therapeutic response of PDAC is influenced by metabolic cross-talk between PDAC and TAMs. Metabolomic profiling of macrophages polarized by PDAC cells in vitro (termed tumor-educated macrophages, or TEMs), classically activated macrophages (M1), and alternatively activated macrophages (M2) revealed that M2 and TEMs produced pyrimidine nucleosides and nucleobases, which were subsequently shown to be directly taken up by PDAC cells. Further, culturing PDAC cells in TEM-conditioned media (CM) resulted in reduced gemcitabine sensitivity, and a screen of individual pyrimidine nucleosides found in CM showed that deoxycytidine alone inhibited gemcitabine in PDAC cells in vitro. Metabolic flux and isotope tracing experiments demonstrated that M2 and TEMs, but not M1 macrophages, utilize glucose carbon for oxidative metabolism and pyrimidine biosynthesis. Inhibition of glucose metabolism in TEMs through several methods that decreased deoxycytidine production, but did not affect TEM proliferation, increased gemcitabine sensitivity in PDAC cells grown in CM from glucose-depleted TEMs. Importantly, addition of exogenous deoxycytidine to these cultures restored gemcitabine resistance of PDAC cells. Deoxycytidine, which is structurally similar to gemcitabine, competed with gemcitabine for activation by the enzyme deoxycytidine kinase (DCK), which is required for the activation of gemcitabine; inhibition of gemcitabine incorporation into PDAC DNA prevented cell death. Depletion or pharmacologic inhibition of myeloid cells in murine models of PDAC enhanced the efficacy of gemcitabine treatment in an immune response–independent manner. These results demonstrate a mechanism of metabolic cross-talk between PDAC and macrophages and suggest targeting of TAMs may improve gemcitabine response in patients with PDAC.

Halbrook CJ, Pontious C, Kovalenko I, Lapienyte L, Dreyer S, Lee H-J, et al. Macrophage-released pyrimidines inhibit gemcitabine therapy in pancreatic cancer. Cell Metabolism 2019 Feb 28 [Epub ahead of print].

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