Lipids and their modifying enzymes regulate diverse features of the tumor microenvironment and cancer progression. The secreted enzyme autotaxin (ATX) hydrolyzes extracellular lysophosphatidylcholine to generate the multifunctional lipid mediator lysophosphatidic acid (LPA) and supports the growth of several tumor types, including pancreatic ductal adenocarcinoma (PDAC). Here we show that ATX suppresses the accumulation of eosinophils in the PDAC microenvironment. Genetic or pharmacologic ATX inhibition increased the number of intratumor eosinophils, which promote tumor cell apoptosis locally and suppress tumor progression. Mechanistically, ATX suppresses eosinophil accumulation via an autocrine feedback loop, wherein ATX–LPA signaling negatively regulates the activity of the AP-1 transcription factor c-Jun, in turn suppressing the expression of the potent eosinophil chemoattractant CCL11 (eotaxin-1). Eosinophils were identified in human PDAC specimens, and rare individuals with high intratumor eosinophil abundance had the longest overall survival. Together with recent findings, this study reveals the context-dependent, immune-modulatory potential of ATX–LPA signaling in cancer.

脂质及其修饰酶调节肿瘤微环境和癌症进展的多种特征。分泌的酶自分泌运动因子 (ATX) 水解细胞外溶血磷脂酰胆碱，生成多功能脂质介质溶血磷脂酸 (LPA)，并支持多种肿瘤类型的生长，包括胰腺导管腺癌 (PDAC)。在这里，我们证明 ATX 抑制 PDAC 微环境中嗜酸性粒细胞的积累。遗传或药理 ATX 抑制增加了肿瘤内嗜酸性粒细胞的数量，从而促进局部肿瘤细胞凋亡并抑制肿瘤进展。从机制上讲，ATX 通过自分泌反馈环路抑制嗜酸性粒细胞积聚，其中 ATX-LPA 信号传导负向调节 AP-1 转录因子 c-Jun 的活性，进而抑制强效嗜酸性粒细胞趋化剂 CCL11（eotaxin-1）的表达。在人类 PDAC 标本中发现了嗜酸性粒细胞，肿瘤内嗜酸性粒细胞丰度高的稀有个体的总生存期最长。结合最近的发现，这项研究揭示了 ATX-LPA 信号在癌症中的背景依赖性免疫调节潜力。