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

Lv, Yi-pin; Tian, Wenqing; Teng, Yong‐Sheng; Wang, Pan; Zhao, Yongliang; Li, Zhengyan; Tang, Shanhong; Chen, Weisan; Xie, Rui; Lü, Muhan; Zhuang, Yuan

doi:10.1016/j.jare.2023.04.013

Cited by 11 publications

(6 citation statements)

References 58 publications

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“…IL-33, a member of the IL-1 family, is implicated in various inflammatory processes, and its roles in gastric diseases are an emerging area of research 32 - 33 . IL-33 serves as a crucial mediator bridging chronic inflammation and metaplasia through promoting proliferation and recruitment of activated eosinophils in a model predisposed to gastritis 34 .…”

Section: Discussionmentioning

confidence: 99%

IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1

Liu,

Huang,

Xiong

et al. 2024

Int. J. Biol. Sci.

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Chronic atrophic gastritis (CAG) is a complex disease characterized by atrophy and inflammation in gastric mucosal tissue, especially with high expression of interleukins. However, the interaction and mechanisms between interleukins and gastric mucosal epithelial cells in CAG remain largely elusive. Here, we elucidate that IL-33 stands out as the predominant inflammatory factor in CAG, and its expression is induced by H. pylori and MNNG through the ROS-STAT3 signaling pathway. Furthermore, our findings reveal that the IL-33/ST2 axis is intricately involved in the progression of CAG. Utilizing phosphoproteomics mass spectrometry, we demonstrate that IL-33 enhances autophagy in gastric epithelial cells through the phosphorylation of AMPK-ULK1 axis. Notably, inhibiting autophagy alleviates CAG severity, while augmentation of autophagy exacerbates the disease. Additionally, ROS scavenging emerges as a promising strategy to ameliorate CAG by reducing IL-33 expression and inhibiting autophagy. Intriguingly, IL-33 stimulation promotes GKN1 degradation through the autolysosomal pathway. Clinically, the combined measurement of IL-33 and GKN1 in serum shows potential as diagnostic markers. Our findings unveil an IL-33-AMPK-ULK1 regulatory mechanism governing GKN1 protein stability in CAG, presenting potential therapeutic targets for its treatment.

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Section: Discussionmentioning

confidence: 99%

IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1

Liu,

Huang,

Xiong

et al. 2024

Int. J. Biol. Sci.

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“…Interestingly, higher mast cell (MC) infiltrates were found in the TLS-low group. Evidence showed that MCs could stimulate regulatory T cells to facilitate GC progression (Lv et al 2023 ). Studies also reported that inhibition of the degranulation of MC attenuated the development of GC, signifying a potential target (Gunjigake et al 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Analyzing the associations between tertiary lymphoid structures and postoperative prognosis, along with immunotherapy response in gastric cancer: findings from pooled cohort studies

Peng,

Wu,

Zhang

et al. 2024

J Cancer Res Clin Oncol

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Background The clinical significance of tertiary lymphoid structure (TLS) in gastric cancer (GC) was uncertain. Methods A systematic search was performed in public databases for eligible studies as of April 2, 2023. Meta-analyses were performed to interrogate the associations between TLS levels and prognosis and immunotherapy response of GC. Bioinformatic analyses based on the nine-gene signature of TLS were further conducted to capture the biological underpinnings. Results Eleven studies containing 4224 GC cases were enrolled in the meta-analysis. TLS levels positively correlated with smaller tumor size, earlier T stage and N stage. Moreover, higher TLS levels were detected in diffuse and mix subtypes of GC (P < 0.001). Higher TLS levels strongly predicted favorable postoperative overall survival of GC, with HR of 0.36 (95%CI 0.26–0.50, P < 0.001) and 0.55 (95%CI 0.45–0.68, P < 0.001) of univariate and multivariate Cox analysis, respectively. Higher TLS levels were also in favor of the treatment response of anti-PD-1 inhibitors as later-line therapy of GC. TLS levels positively correlated with immune effector cells infiltration, diversity and richness of T cell receptor and B cell receptor repertoire, immune checkpoint genes expression, and immune-related genes mutation of GC in the TCGA-STAD cohort, representing higher immunogenicity and immunoactivity. Moreover, moderate accuracy of TLS levels in predicting benefit from anti-PD-1 inhibitors in the PRJEB25780 cohort was also validated (AUC 0.758, 95%CI 0.583–0.933), higher than the microsatellite instability-score and Epstein-Barr virus status. Conclusions TLS levels demonstrated potential in predicting the postoperative prognosis and immunotherapy response of GC.

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“…Furthermore, IL-33 stimulation, in vitro, induces mast cells to release IL-2, which, in turn, promotes the differentiation and expansion of ICOS + Tregs that inhibit CD8 + T cells. Notably, in a xenograft gastric cancer model adopting NOD/SCID mice, this IL-33/IL-2-dependent activation of ICOS + Tregs is shown to promote tumor growth and progression [128].…”

Section: Cell Types Associated With the Cascade Of Events Leading To ...mentioning

confidence: 99%

The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer

Privitera,

Williams,

De Salvo

2024

Cancers

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Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.

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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

Cited by 11 publications

References 58 publications

IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1

IL-33 Accelerates Chronic Atrophic Gastritis through AMPK-ULK1 Axis Mediated Autolysosomal Degradation of GKN1

Analyzing the associations between tertiary lymphoid structures and postoperative prognosis, along with immunotherapy response in gastric cancer: findings from pooled cohort studies

The Importance of Th2 Immune Responses in Mediating the Progression of Gastritis-Associated Metaplasia to Gastric Cancer

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