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

ABSTRACT:

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.

SUBMITTER: Lv Y 

PROVIDER: S-EPMC10918354 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature