Gastric Cancer Cell-Derived Kynurenines Hyperactive Regulatory T Cells to Promote Chemoresistance via the IL-10/STAT3/BCL2 Signaling Pathway

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Abstract
Chemotherapy resistance is frequently observed in gastric cancer patients and is associated with poor prognosis; tryptophan (Trp) catabolism has been recognized as a key metabolic regulator of many types of cancer progression. Regulatory T cells (Tregs) and Trp metabolite kynurenine (Kyn) were analyzed using tumor tissues. Chemotherapy resistance induced by IL-10 or Treg was detected by flow cytometry assay. The activation of STAT3/BCL2 signaling pathways in gastric cells cocultured by Treg was illustrated by western blotting. Patients' Treg and human gastric cancer organoid model were established to examine the anticancer effects of STAT3 inhibitor. We found that a higher level of IL-10 secreted by Kyn-induced Tregs was responsible for the 5-fluorouracil-induced resistance of gastric cancer cell lines. STAT3 and BCL2 knockout significantly abrogated Treg supernatant- or IL-10-induced chemoresistance in SGC7901 and BGC823 cell lines. Furthermore, STAT3 inhibitor significantly reduced the organoid and clonogenicity of organoids cocultured with Treg. Our data suggested that tumor-derived Kyn may hyperactivate Tregs and induce chemoresistance through the IL-10/STAT3/BCL2 signaling pathway.

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