近日，美国密歇根大学Costas A. Lyssiotis研究团队发现巨噬细胞通过释放嘧啶来增加胰腺癌对吉西他滨疗法的耐药性。该项研究成果发表在2019年6月4日出版的《Cell Metabolism》上。

研究人员通过分析代谢产物交换发现，被PDA细胞重编程的巨噬细胞能够分泌包括脱氧胞苷在内的一系列的嘧啶类分子。由于结构的相似性，这些分泌的产物能够在药物摄入与代谢水平的分子竞争机制来抑制吉西他滨发挥功能。因此，在PDA小鼠模型中，通过遗传或药物手段来对去除TAMs能够增加肿瘤细胞对吉西他滨的敏感性。与此一致的是，巨噬细胞浸润较少的肿瘤病人对吉西他滨疗法有更好的响应。尽管目前对于免疫细胞中这种嘧啶交换在生理中的功能未知，但研究人员表示其发现的嘧啶分泌是巨噬细胞选择性活化后的一个基础功能。这些发现为了解巨噬细胞在胰腺癌治疗中的作用提供了见解，并有可能为未来的治疗提供参考。

肿瘤相关巨噬细胞(TAMs)大量浸润是胰腺导管腺癌(PDA)的主要特点之一。据报道，TAMs可引起肿瘤细胞对吉西他滨(用于治疗PDA的一线化疗药物)的耐药性，但其背后的机制尚不清楚。

附：英文原文


Title: Macrophage-Released Pyrimidines Inhibit Gemcitabine Therapy in Pancreatic Cancer

Author: Christopher J. Halbrook, Corbin Pontious, Ilya Kovalenko, Jennifer P. Morton, Marina Pasca di Magliano, Costas A. Lyssiotis

Issue&Volume: Jun 04, 2019 Volume 29Issue 6

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.

DOI: https://doi.org/10.1016/j.cmet.2019.02.001

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(19)30065-8