Tumor-infiltrating mast cells stimulate ICOS+ regulatory T cells through an IL-33 and IL-2 axis to promote gastric cancer progression
Tumor-infiltrating mast cells stimulate ICOS+ regulatory T cells through an IL-33 and IL-2 axis to promote gastric cancer progression
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DOI：
10.1016/j.jare.2023.04.013
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发表时间：
2024-02-28
影响因子：
10.7
通讯作者：
Zhuang，Yuan
中科院分区：
文献类型：
--
作者：
Lv，Yipin;Tian，Wenqing;Zhuang，Yuan
在实体瘤中，调节性T细胞（Treg）和肥大细胞根据微环境的不同发挥不同的作用。方法对98例胃癌患者进行肥大细胞计数、ICOS + Treg细胞计数、IL-33/IL-2轴表达、IL-33/IL-2/以及IL-33或IL-2的水平。结果胃癌患者肿瘤组织中IL-33的产生明显高于正常对照组，肿瘤组织中IL-33的产生明显高于正常对照组，肿瘤组织中IL-33的产生明显高于正常对照组。肿瘤源性IL-33刺激的肥大细胞通过IL-33介导的细胞凋亡抑制表现出延长的寿命。此外，由肿瘤来源的IL-33刺激的肥大细胞分泌IL-2，其诱导Treg扩增。这些诱导型T细胞显示出活化的免疫抑制表型，具有诱导型T细胞共刺激分子（ICOS）的阳性表达。在体外，IL-2从IL-33刺激的肥大细胞诱导ICOS+ T细胞的数量增加，对CD 8 +T细胞的增殖和效应功能的免疫抑制活性增加。在体内，用抗IL-2中和抗体处理ICOS+ TCR 4后，再联合CD 8 +T细胞注射GC小鼠模型，结果显示ICOS+ TCR 4细胞浸润增加，效应分子产生增加，肿瘤生长和进展受到抑制。此外，减少GC患者的生存与肿瘤源性ICOS+ Tclime.ConclusionOur结果突出了GC浸润肥大细胞和ICOS+ Tclime. ConclusionOur结果之间的串扰，并提供了一种新的机制，描述ICOS+调节性T细胞扩增和诱导的IL-33/肥大细胞/IL-2信号轴在GC中，也提供了功能的证据，这种免疫抑制途径的调制可以减弱GC介导的免疫耐受。
IntroductionIn 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.ObjectiveThe 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.MethodsAnalyses 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 abilitiesin vitroandin vivo.ResultsGC 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 cell infiltration and effector molecules production, meanwhile tumor growth and progression were inhibited. Besides, reduction in GC patient survival was associated with tumor-derived ICOS+Tregs.ConclusionOur results highlight a crosstalk between GC-infiltrating mast cells and ICOS+Tregs and provide a novel mechanism describing ICOS+Treg expansion and induction by an IL-33/mast cell/IL-2 signaling axis in GC, and also provide functional evidence that the modulation of this immunosuppressive pathway can attenuate GC-mediated immune tolerance.