| Autor: |
Yipin Lv, Wenqing Tian, Yongsheng Teng, Pan Wang, Yongliang Zhao, Zhengyan Li, Shanhong Tang, Weisan Chen, Rui Xie, Muhan Lü, Yuan Zhuang |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Journal of Advanced Research, Vol 57, Iss , Pp 149-162 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
2090-1232 |
| DOI: |
10.1016/j.jare.2023.04.013 |
| Popis: |
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 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. 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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