IL‐33/ST2 as a potential target for tumor immunotherapy

Jiang, Wen-Yi; Lian, Jingyao; Ye, Ying; Zhang, Yi

doi:10.1002/eji.202149175

Cited by 31 publications

(20 citation statements)

References 122 publications

(187 reference statements)

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“…Incidentally, AstraZeneca is conducting the trial of a monoclonal antibody called MEDI3506 (anti-IL-33) in patients with diabetic nephropathy. However, this trial has not yet been completed (Jiang et al, 2021). It is known that the main side effect of monoclonal antibody administration is the risk of an adverse immune response (Hansel et al, 2010;Liu and Li, 2014).…”

Section: The Potential Value Of the Il-33/ St2 Pathway For Renal Fibrosismentioning

confidence: 99%

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Tan

Jing

2022

Front. Physiol.

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Chronic kidney disease (CKD) is a major public health problem that affects more than 10% of the population worldwide and has a high mortality rate. Therefore, it is necessary to identify novel treatment strategies for CKD. Incidentally, renal fibrosis plays a central role in the progression of CKD to end-stage renal disease (ESRD). The activation of inflammatory pathways leads to the development of renal fibrosis. In fact, interleukin-33 (IL-33), a newly discovered member of the interleukin 1 (IL-1) cytokine family, is a crucial regulator of the inflammatory process. It exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Although the role of this pathway in cardiac, pulmonary, and hepatic fibrotic diseases has been extensively studied, its precise role in renal fibrosis has not yet been completely elucidated. Recent studies have shown that a sustained activation of IL-33/ST2 pathway promotes the development of renal fibrosis. However, with prolonged research in this field, it is expected that the IL-33/ST2 pathway will be used as a diagnostic and prognostic tool for renal diseases. In addition, the IL-33/ST2 pathway seems to be a new target for the future treatment of CKD. Here, we review the mechanisms and potential applications of the IL-33/ST2 pathway in renal fibrosis; such that it can help clinicians and researchers to explore effective treatment options and develop novel medicines for CKD patients.

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Section: The Potential Value Of the Il-33/ St2 Pathway For Renal Fibrosismentioning

confidence: 99%

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Tan

Jing

2022

Front. Physiol.

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“…IL‐33 exert both protumor and antitumor effects, depending mainly on the host's tumor immune microenvironment, but also on the tissue source of IL‐33. In general, IL‐33 of tumor tissue origin exerts antitumor effects by promoting the local aggregation of NK cells, CD8+ T cells, ILC2 and eosinophils in the tumor, whereas IL‐33 of tumor stromal cell origin exerts protumor effects by promoting the local aggregation of Tregs and MDSCs in the tumor 52,53 . The study demonstrated that IL‐33 expression in cytoplasm of tumor was significantly and positively correlated with CD3 + /CD8 + T lymphocytes.…”

Section: Discussionmentioning

confidence: 89%

“…was more likely to be expressed in the cytoplasm of tumor cells in in the tumor. 52,53 The study demonstrated that IL-33 expression in cytoplasm of tumor was significantly and positively correlated with CD3 + /CD8 + T lymphocytes. Our results preliminarily showed that the tumor-derived IL-33 may played an antitumor role, which promote the infiltration of T lymphocytes in tumor.…”

Section: Discussionmentioning

confidence: 96%

Relationship and prognostic significance of IL-33, PD-1/PD-L1, and tertiary lymphoid structures in cervical cancer

Zhang

Yang

et al. 2022

Journal of Leukocyte Biology

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IL‐33, an epithelial‐derived cytokine, functions as an alarmin for the immune system in the tumor microenvironment (TME). However, the expression and role of IL‐33 on cervical cancer remain unclear. The aim of this study was to investigate the expression of IL‐33 and its relationship with clinicopathologic features, tertiary lymphoid structures (TLS), and programmed cell death 1 (PD‐1)/programmed cell death 1 ligand (PD‐L1) immune checkpoints by immunohistochemistry in 93 cervical cancer patient specimens. Down‐regulation of IL‐33 expression was observed in tumor tissues compared with adjacent tissues. More importantly, IL‐33 was detected in the cytoplasm of tumor fraction. IL‐33 expression in tumor cytoplasm was associated with tumor size and the invasive depth of tumors (p < 0.05). Meanwhile, IL‐33 expression in tumor cytoplasm was positively correlated with infiltration of CD3+ T cells, CD8+ T cells, and PD‐L1 expression in tumor tissues (p < 0.05). The number of TLS strongly correlated with the depth of tumor invasion, preoperative chemotherapy, human papillomavirus infection, and high level of PD‐1 (p < 0.05). However, there was no significant relationship between IL‐33 and TLS. Kaplan–Meier survival curves showed that the formation of TLS was associated with a better prognosis (p = 0.008). In multivariable Cox regression modeling, high expression of PD‐L1 in tumor tissues was correlated with poor prognosis (HR = 0.128; 95% CI: 0.026–0.646; p = 0.013), whereas the high expression of IL‐33 in tumor tissues was associated with better prognosis (HR = 5.097; 95% CI:1.050–24.755; p = 0.043). These results indicate that IL‐33, TLS, and PD‐L1 are potentially valuable prognostic predictor for cervical cancer. IL‐33 has potential for combination with PD‐L1‐related antitumor therapy.

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“…Proof-of-concept is provided in clinical studies with the IL-33 antibody etokimab, and with the ST2 antibody astegolimab showing improvement in patients with atopic dermatitis [ 75 ], a peanut allergy [ 76 ], or severe asthma [ 77 ]. Therapeutic strategies for targeting IL-33/ST2 signaling for the treatment of various inflammatory diseases are evolving [ 78 , 79 ]. However, additional studies are required to establish that blocking the IL33/ST2 axis may have therapeutic potential for MCC treatment.…”

Section: Discussionmentioning

confidence: 99%

The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma

Rasheed

Moens

Policastro

et al. 2022

IJMS

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Merkel cell polyomavirus (MCPyV) is a causal factor in Merkel cell carcinoma (MCC). The oncogenic potential is mediated through its viral oncoproteins large T-antigen (LT) and small T-antigen (sT). Cytokines produced by tumor cells play an important role in cancer pathogenesis, and viruses affect their expression. Therefore, we compared human cytokine and receptor transcript levels in virus positive (V+) and virus negative (V−) MCC cell lines. Increased expression of IL-33, a potent modulator of tumor microenvironment, was observed in V+ MCC cell lines when compared to V− MCC-13 cells. Transient transfection studies with luciferase reporter plasmids demonstrated that LT and sT stimulated IL-33, ST2/IL1RL1 and IL1RAcP promoter activity. The induction of IL-33 expression was confirmed by transfecting MCC-13 cells with MCPyV LT. Furthermore, recombinant human cytokine domain IL-33 induced activation of MAP kinase and NF-κB pathways, which could be blocked by a ST2 receptor antibody. Immunohistochemical analysis demonstrated a significantly stronger IL-33, ST2, and IL1RAcP expression in MCC tissues compared to normal skin. Of interest, significantly higher IL-33 and IL1RAcP protein levels were observed in MCC patient plasma compared to plasma from healthy controls. Previous studies have demonstrated the implication of the IL-33/STL2 pathway in cancer. Because our results revealed a T-antigens-dependent induction of the IL-33/ST2 axis, IL-33/ST2 may play a role in the tumorigenesis of MCPyV-positive MCC. Therefore, neutralizing the IL-33/ST2 axis may present a novel therapeutic approach for MCC patients.

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IL‐33/ST2 as a potential target for tumor immunotherapy

Cited by 31 publications

References 122 publications

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Interleukin-33/ Suppression of Tumorigenicity 2 in Renal Fibrosis: Emerging Roles in Prognosis and Treatment

Relationship and prognostic significance of IL-33, PD-1/PD-L1, and tertiary lymphoid structures in cervical cancer

The Merkel Cell Polyomavirus T-Antigens and IL-33/ST2-IL1RAcP Axis: Possible Role in Merkel Cell Carcinoma

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