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

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Tumor-infiltrating mast cells stimulate ICOS+ regulatory T cells through an IL-33 and IL-2 axis to promote gastric cancer progression
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2023-04-20 , DOI: 10.1016/j.jare.2023.04.013
Yipin Lv ₁ , Wenqing Tian ₂ , Yongsheng Teng ₃ , Pan Wang ₃ , Yongliang Zhao ₄ , Zhengyan Li ₄ , Shanhong Tang ₅ , Weisan Chen ₆ , Rui Xie ₇ , Muhan Lü ₈ , Yuan Zhuang ₉

Affiliation

Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu, Sichuan, China; National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China.
Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China.
The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, China.
Department of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China.
Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu, Sichuan, China.
La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Victoria, Australia.
The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China.
Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China.
The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China; Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China; National Engineering Research Center of Immunological Products, Department of Microbiology and Biochemical Pharmacy, College of Pharmacy and Laboratory Medicine, Third Military Medical University, Chongqing, China.

Introduction

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.

Objective

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.

Methods

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.

Results

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-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.

Conclusion

Our 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.

中文翻译：

肿瘤浸润肥大细胞通过 IL-33 和 IL-2 轴刺激 ICOS+ 调节性 T 细胞，促进胃癌进展

介绍

在实体瘤中，调节性 T 细胞 (Treg) 和肥大细胞根据微环境发挥不同的作用。然而，胃癌 (GC) 中肥大细胞和 Treg 介导的相互作用以及它们的调节、功能和临床意义尚不清楚。

客观的

本研究证明了肿瘤浸润肥大细胞通过IL-33/IL-2轴刺激ICOS ⁺调节性T细胞促进胃癌生长的机制。

方法

对 98 名 GC 患者进行了分析，以检查肥大细胞计数、ICOS ⁺ Tregs 以及 IL-33 或 IL-2 水平。对分离的 ICOS ⁺ Treg 和 CD8 ⁺ T 细胞进行刺激、培养并测试其体外和体内功能。

结果

胃癌患者的肿瘤中 IL-33 的产生显着增加。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，肿瘤来源的 IL-33 刺激肥大细胞分泌 IL-2，从而诱导 Treg 扩增。这些可诱导的 Tregs 显示出激活的免疫抑制表型，并可诱导 T 细胞共刺激因子 (ICOS) 呈阳性表达。在体外，来自 IL-33 刺激的肥大细胞的 IL-2 诱导 ICOS ⁺ Tregs 数量增加，并增加针对 CD8 ⁺ T 细胞增殖和效应功能的免疫抑制活性。在体内，GC小鼠模型中，用抗IL-2中和抗体处理ICOS ⁺ Tregs，然后与CD8 ⁺ T细胞共注射，结果显示CD8 ⁺ T细胞浸润和效应分子产生增加，同时肿瘤生长和进展被抑制。此外，GC 患者生存率的降低与肿瘤衍生的 ICOS ⁺ Tregs 相关。