Tumor-infiltrating mast cells stimulate ICOS+ regulatory T cells through an IL-33 and IL-2 axis to promote gastric cancer progression

作者：Yi-pin Lv, Wenqing Tian, Yong‐sheng Teng, Pan Wang, Yongliang Zhao, Zhengyan Li, Shanhong Tang, Weisan Chen, Rui Xie, Muhan Lü, Yuan Zhuang · 发表于：Journal of Advanced Research · 年份：2023 · DOI：10.1016/j.jare.2023.04.013 · 被引用次数：51 · 研究领域：IL-33, ST2, and ILC Pathways、Immune Cell Function and Interaction、Mast cells and histamine

In solid tumors, regulatory T cell (Treg) and mast cell perform different roles depending on the microenvironment. Nevertheless, mast cell and Treg-mediated interactions in gastric cancer (GC) are unclear, as are their regulation, function, and clinical significance. The present study demonstrated the mechanism of tumor-infiltrating mast cells stimulating ICOS+ regulatory T cells via the IL-33/IL-2 axis to promote the growth of gastric cancer. Analyses of 98 patients with GC were conducted to examine mast cell counts, ICOS+ Tregs, and the levels of IL-33 or IL-2. Isolated ICOS+ Treg and CD8+ T cell were stimulated, cultured and tested for their functional abilities in vitro and in vivo. GC patients exhibited a significantly more production of IL-33 in tumors. Mast cell stimulated by tumor-derived IL-33 exhibited a prolonged lifespan through IL-33 mediated inhibition of apoptosis. Moreover, mast cells stimulated by tumor-derived IL-33 secreted IL-2, which induced Treg expansion. These inducible Tregs displayed an activated immunosuppressive phenotype with positive expression for the inducible T cell co-stimulator (ICOS). In vitro, IL-2 from IL to 33-stimulated mast cells induced increased numbers of ICOS+ Tregs with increased immunosuppressive activity against proliferation and effector function of CD8+ T cell. In vivo, ICOS+ Tregs were treated with anti-IL-2 neutralizing antibody followed by co-injection with CD8+ T cells in GC mouse model, which showed an increased CD8+ T ce...