Abstract：
:Dysregulation of Wnt/β-catenin signaling is frequently observed in human gastric cancer. Elucidation of the tumor immune microenvironment is essential for understanding tumorigenesis and for the development of immunotherapeutic strategies. However, it remains unclear how β-catenin signaling regulates the tumor immune microenvironment in the stomach. Here, we identify CCL28 as a direct transcriptional target gene of β-catenin/T-cell factor (TCF). Protein levels of β-catenin and CCL28 positively correlated in human gastric adenocarcinoma. β-Catenin-activated CCL28 recruited regulatory T (Treg) cells in a transwell migration assay. In a clinically relevant mouse gastric cancer model established by Helicobacter (H.) felis infection and N-methyl-N-nitrosourea (MNU) treatment, inhibition of β-catenin/TCF activity by a pharmacologic inhibitor iCRT14 suppressed CCL28 expression and Treg cell infiltration in the stomach. Moreover, an anti-CCL28 antibody attenuated Treg cell infiltration and tumor progression in H. felis/MNU mouse models. Diphtheria toxin-induced Treg cell ablation restrained gastric cancer progression in H. felis/MNU-treated DEREG (Foxp3-DTR) mice, clarifying the tumor-promoting role of Treg cells. Thus, the β-catenin-CCL28-Treg cell axis may serve as an important mechanism for immunosuppression of the stomach tumor microenvironment. Our findings reveal an immunoregulatory role of β-catenin signaling in stomach tumors and highlight the therapeutic potential of CCL28 blockade for the treatment of gastric cancer. SIGNIFICANCE: These findings demonstrate an immunosuppressive role of tumor-intrinsic β-catenin signaling and the therapeutic potential of CCL28 blockade in gastric cancer.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Ji L,Qian W,Gui L,Ji Z,Yin P,Lin GN,Wang Y,Ma B,Gao WQdoi
10.1158/0008-5472.CAN-19-3074subject
Has Abstractpub_date
2020-05-15 00:00:00pages
2004-2016issue
10eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-19-3074journal_volume
80pub_type
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