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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

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机构： [1]Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu, Sichuan, China [2]Department of Gastroenterology, Chongqing University Cancer Hospital, Chongqing, China [3]The 940th Hospital of Joint Logistics Support Force of PLA, Lanzhou, China [4]Department of General Surgery and Centre of Minimal Invasive Gastrointestinal Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China [5]La Trobe Institute of Molecular Science, La Trobe University, Bundoora, Victoria, Australia [6]The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China [7]Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China [8]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

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关键词： Gastric cancer IL-33 Mast cells IL-2 ICOS+ regulatory T cells

摘要：

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-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.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.Copyright © 2023. Production and hosting by Elsevier B.V.

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出版当年[2023]版：

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第一作者：

第一作者机构： [1]Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu, Sichuan, China [8]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 [*4]Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu 610083, 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 400038, China

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通讯作者：

通讯机构： [1]Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu, Sichuan, China [6]The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi, Guizhou, China [7]Department of Gastroenterology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China [8]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 [*1]The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi 563003, Guizhou, China. Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 6460, 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 400038, China [*2]Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou 64600, Sichuan, China [*3]The Collaborative Innovation Center of Tissue Damage Repair and Regeneration Medicine of Zunyi Medical University, Zunyi 563003, Guizhou, China [*4]Department of Digestive Diseases, The General Hospital of Western Theater Command, Chengdu 610083, 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 400038, China

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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

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