PPARδ dysregulation of CCL20/CCR6 axis promotes gastric adenocarcinoma carcinogenesis by remodeling gastric tumor microenvironment

• DOI: 10.1007/s10120-023-01418-w
• Publication Date: 2023-08-12T06:01:47Z
• Authors: Yi Liu; Daoyan Wei; Yasunori Deguchi; Weiguo Xu; Rui Tian; Fuyao Liu; Min Xu; Fei Mao; Donghui Li; Weidong Chen; Lovie Ann Valentin; Eriko Deguchi; James C. Yao; Imad Shureiqi; Xiangsheng Zuo
• Keywords: Receptors, CCR6; Mice; Chemokine CCL20; Stomach Neoplasms; Carcinogenesis; Tumor Microenvironment; Humans; Animals; Original Article; PPAR delta; CD8-Positive T-Lymphocytes; Adenocarcinoma

Abstract Background Peroxisome proliferator-activated receptor delta (PPARδ) promotes inflammation and carcinogenesis in many organs, but the underlying mechanisms remains elusive. In stomachs, PPARδ significantly increases chemokine Ccl20 expression in gastric epithelial cells while inducing gastric adenocarcinoma (GAC). CCR6 is the sole receptor of CCL20. Here, we examine the role of PPARδ–mediated Ccl20/Ccr6 signaling in GAC carcinogenesis and investigate the underlying mechanisms.

Methods The effects of PPARδ inhibition by its specific antagonist GSK3787 on GAC were examined in the mice with villin-promoter–driven PPARδ overexpression (PpardTG). RNAscope Duplex Assays were used to measure Ccl20 and Ccr6 levels in stomachs and spleens. Subsets of stomach-infiltrating immune cells were measured via flow cytometry or immunostaining in PpardTG mice fed GSK3787 or control diet. A panel of 13 optimized proinflammatory chemokines in mouse sera were quantified by an enzyme-linked immunosorbent assay.

Results GSK3787 significantly suppressed GAC carcinogenesis in PpardTG mice. PPARδ increased Ccl20 level to chemoattract Ccr6+ immunosuppressive cells, including tumor-associated macrophages, myeloid-derived suppressor cells and T regulatory cells, but decreased CD8+ T cells in gastric tissues. GSK3787 suppressed PPARδ–induced gastric immunosuppression by inhibiting Ccl20/Ccr6 axis. Furthermore, Ccl20 protein levels increased in sera of PpardTG mice starting at the age preceding gastric tumor development and further increased with GAC progression as the mice aged. GSK3787 decreased the PPARδ-upregulated Ccl20 levels in sera of the mice.

Conclusions PPARδ dysregulation of Ccl20/Ccr6 axis promotes GAC carcinogenesis by remodeling gastric tumor microenvironment. CCL20 might be a potential biomarker for the early detection and progression of GAC.