The role of IL-33/ST2 signaling in the tumor microenvironment and Treg immunotherapy

Abstract

Interleukin (IL)-33 is a tissue-derived nuclear cytokine belonging to the IL-1 family. Stimulation-2 (ST2) is the only known IL-33 receptor. ST2 signals mostly on immune cells found within tissues, such as regulatory T cells (Treg cells), CD8+ T cells, and natural killer (NK) cells. Therefore, the IL-33/ST2 signaling pathway is important in the immune system. IL-33 deficiency impairs Treg cell function. ST2 signaling is also increased in active Treg cells, providing a new approach for Treg-related immunotherapy. The IL-33/ST2 signaling pathway regulates multiple immune-related cells by activating various intracellular kinases and factors in the tumor microenvironment (TME). Here, we review the latest studies on the role of the IL-33/ST2 signaling pathway in TME and Treg immunotherapy.

Keywords

Biology cancer interleukin-33 regulatory T cell stimulation-2 tumor microenvironment

Impact Statement

This review will be helpful in understanding the importance of the interleukin (IL)-33/Stimulation-2 (ST2) signaling pathway in immunotherapy and its role in a wide range of diseases. Understanding the relationship between IL-33/ST2 signaling and the tumor microenvironment and Treg immunotherapy is important, as it is undoubtedly a potential target for immunotherapy and clinical diseases.

Introduction

Regulatory T cells (Treg cells) are a T cell subset with immunosuppressive functions. These cells are found in almost all tissues and regulate several cell types involved in innate and adaptive immunity. They inhibit the immune response in the body, maintain immune balance, and prevent autoimmune diseases. Treg cells are generated in the thymus and migrate to peripheral tissues and organs. Treg cells have been shown to inhibit the activation and proliferation of potential autoreactive T cells in normal environments, which influence immunoregulation capability. Treg cells are characterized by expression of forkhead box protein P3 (FOXP3). Since their discovery in early 1995, Treg cells are marked by CD4⁺ CD25⁺ FOXP3⁺ status.^1,2 Treg cells can be divided into natural regulatory T cells (nTregs) and peripherally induced T cells (pTregs). Expression of helios is a marker of nTregs that distinguishes these cells from pTregs.³

Treg cells function through a variety of mechanisms: direct inhibition or lysis of target cells; inhibition of antigen-presenting cell maturation; secretion of anti-inflammatory cytokines, such as tumor growth factor (TGF)-β and interleukin (IL)-10; and negative regulation of cell-surface receptors, such as cytotoxic T lymphocyte antigen 4 (CTLA-4), CD39, and CD73. Thus, they participate in the regulation of inflammation and various immune diseases.⁴ Treg cells form a heterogeneous population, exhibiting different migratory and immunomodulatory properties. They have shown promise as therapeutic targets in the fields of inflammation, tumor escape mechanisms, and immunotherapy.^5,6 Immune escape is one of the important causes of tumor development. Treg cell numbers and functions are upregulated in tumors and in the microenvironment, which further reinforce their immunosuppressive effect in promoting tumor development.⁶ The use of immune checkpoint therapies has brought new possibilities for tumor therapy, as these agents regulate Treg cells in various ways to deplete or block Treg cells.⁷

As a member of the interleukin (IL)-1 family, IL-33 is strongly expressed in endothelial cells, epithelial cells, and fibroblasts, activating immune cells expressing the Stimulation-2 (ST2) receptor, such as Treg cells, NK cells, and CD8⁺ T cells.⁸ IL-33 exerts its activity through a heterodimeric receptor consisting of its primary receptor ST2 and an accessory receptor, the IL-1 receptor (IL1RAP). IL-33 amplifies Treg cells by inhibiting effector T cells, but also by inhibiting the production of interferon (IFN)-γ by CD8⁺ T cells.⁹ As a proinflammatory factor, IL-33 mediates antitumor immune activity through Th1 and NK cells and participates in a tumor immune escape mechanisms through T helper (Th)2 and Treg cells. IL-33 also promotes the activation of myeloid suppressor cells (MDSCs), innate lymphoid cells (ILC)-2, CD8⁺ T cells, and dendritic cells (DCs).^9–12

ST2 is expressed more frequently in Treg cells than in non-immune cells.¹³ There are three main subtypes of ST2: ST2L (transmembrane type), sST2 (soluble type), and ST2V (suppression of tumorigenicity 2-variant).^14,15 ST2L binds to the alarmin IL-33 to trigger downstream signaling. sST2 negatively regulates the IL-33/ST2 signaling pathway by acting as a decoy receptor to prevent IL-33/ST2L binding.^16,17

In this review, we summarize the findings of recent studies on the role of the IL-33/ST2 signaling pathway in tumor microenvironment (TME) and Treg cell-related immunotherapy.

The role of IL-33/ST2 signaling in the tumor microenvironment

Effect of IL-33/ST2 signaling on Treg cells

As a proinflammatory factor, IL-33 expresses an antitumor immune response through Th1 cells and NK cells, and plays a role in the tumor immune escape mechanism through Th2 cells and Treg cells, promoting the activation of MDSCs, intervening in ILC-2 cells, CD8⁺ T cells, and DCs.^18,19 IL-33 is involved in maintaining FOXP3⁺ Treg cell homeostasis at mucosal sites and directly induces the proliferation of FOXP3⁺ Treg cells and enhances their immunosuppressive capacity.^20,21 At a steady state, ST2⁺ Treg cells represent the majority of ST2-expressing CD4⁺ T cells. IL-33 is dispensable for the production, maintenance, and tissue accumulation of ST2⁺ Treg cells. Conventional mouse CD11c⁺ DCs are stimulated by IL-33. These cells then secrete IL-2, leading to selective amplification of ST2⁺-inhibitory CD4⁺ FOXP3⁺ Treg.⁹ ST2⁺ Treg cells inhibit CD4⁺ T cell proliferation in vitro, independently of IL-33, and this inhibitory capacity is mediated partly by the enhanced production and activation of the anti-inflammatory cytokines IL-10 and TGF-β.²² Moreover, IL-33/ST2 signaling enhances the activity of GATA-3 and STAT5, and recruits GATA-3 and RNA polymerase II to the FOXP3 promoter and IL1RL1 sites. Thus, IL-33 not only indirectly promotes FOXP3 production but also enhances the expression of its receptors.

IFN-γ is secreted by CD4 Th1 and CD8 cytotoxic T cells, which have a direct antiviral replication effect and are important activators of macrophages. IFN-γ expression is downregulated in the TME. As a factor that affects Treg cell function, IFN-γ affects Treg cell function by making these cells fragile, leading to the weakening of Treg function and thus alleviating immune suppression and immune cell function in the TME.²³ As early as 2008, IL-33 was found to enhance antigen-dependent and antigen-independent T-cell responses, including IL-5, IL-13, and IFN-γ production. IL-33 is a pleiotropic cytokine that acts similar to IL-18 under certain conditions, promoting IFN-γ production and type 1 immunity.^24,25

According to the literature, in colonic Treg cells, IL-33/ST2 signaling can promote the expression of FOXP3⁺ and promote the function of Treg cells by promoting TGF-β1-mediated differentiation.²⁶ At present, it remains unclear whether FOXP3⁺ promotes antitumor immune function and combination therapy. A more in-depth understanding of Treg cells is necessary.^27,28

A major hallmark of T-cell exhaustion is the enhanced expression of multiple immune checkpoint proteins, including programmed cell death protein 1 (PD-1), CTLA-4, lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and ITIM domain (TIGIT), and T cell immunoglobulin-3 (TIM-3).²⁹ In the tumor-infiltrating environment, T cells play a tumor-killing role, and a large number of Treg cells infiltrate tumor tissues where they exert an immunosuppressive function. Tumor-infiltrating Treg cells are mostly activated and rapidly reproduce. These cells express high levels of cell surface molecules associated with T-cell activation, such as CD25, CTLA-4, PD-1, LAG3, TIGIT, ICOS, and TNF receptor superfamily members, including 4-1BB, OX-40, and GITR (GRAPH1).³⁰ Increasing evidence suggests that the removal of Treg cells can induce and enhance antitumor immune responses. However, the unselective removal of large numbers of Treg cells may simultaneously trigger harmful autoimmunity.³¹

Effector Treg cells are the major cell type in tumor tissues. These effector Treg cells specifically express various cell surface molecules, including chemokine receptors, such as CCR4. Blocking of candidate molecules on effector Treg cells by using specific monoclonal antibodies is a potential approach to ameliorate tumor progression. Furthermore, CTLA-4 is strongly expressed on effector Treg cells, causing active proliferation and apoptosis, and is used to control their function specifically. Immune checkpoint therapy is a rising research direction in cancer immunotherapy recently. Targeting PD-1 and CTLA-4, which are expressed on Treg cells, has resulted in a better outcome in cancer patients. CTLA-4, which is expressed on tumor-infiltrating Treg cells, downregulates the expression of antigen-presenting cells and CD80/CD86 co-stimulatory molecules on DCs, thereby preventing the activation of conventional T cells. Blocking immune checkpoints, including CTLA-4 and PD-1, in vivo has been shown to promote antitumor immunity by inhibiting Treg cells and enhancing effector T-cell function. In the TME, PD-1 is expressed on Treg cells and binds to PD-L1 expressed by tumor cells. This suppresses T-cell function, aggravating immunosuppression and promoting cancer development (Figure 1).³²

Figure 1.

The figure shows the influence of IL-33/ST2 axis on Treg cells and surface molecules under normal physiological state and TME. In physiological state, IL-33/ST2 mainly maintains the balance of ST2⁺ Treg cells and maintains autoimmunity. In the TME, Treg cells surface molecular activity increased, such as CTLA-4 and PD-1. IL-33/ST2 may increase this risk and further enhance the number of Treg cells to inhibit T cell proliferation and activity (left). Inhibition of IL-33/ST2 axis and surface molecules could restore the number and activity of some T cells (right). (A color version of this figure is available in the online journal.)

Effect of IL-33/ST2 signaling on angiogenesis in the tumor microenvironment

Blood vessels are essential for tumor survival and development. During the occurrence and development of tumors, blood vessels supply large amounts of nutrients to the tumors and ensure the continuous existence of the TME.³³ The TME consists of tumor cells, surrounding cells, and secreted factors. Different TMEs have different backgrounds; therefore, IL-33/ST2 signaling may play various roles in tumor angiogenesis. IL-33 is a potent endothelial activator in blood vessels that promotes angiogenesis and vascular permeability. IL-33 regulates angiogenesis by promoting endothelial cell proliferation, differentiation, and morphological changes. These effects are inhibited by ST2 deficiency in vivo. In addition, IL-33/ST2 signaling increases endothelial permeability, downregulates occludin and VE-cadherin expression at mRNA level, and increases ICAM-1 expression. IL-33/ST2 signaling specifically disrupts the stability of the endothelial barrier, affects angiogenesis, and plays an important role in the TME.^33–36

Effect of IL-33/ST2 signaling on natural killer cells in the tumor microenvironment

CD8⁺ T and natural killer (NK) cells are effective tumor-killing cells. In the TME, the number of these cells is reduced and their functions are inhibited, leading to aggressive tumor proliferation and progression.³⁷ IL-33/ST2 signaling can activate and recruit NK cells into the TME to clear tumor cells effectively and to reconstruct the microenvironment further.³⁸ IL-33/ST2 signaling is closely associated with NK cells and can induce NK cells to produce IFN-γ and release perforin and granzymes to kill tumor cells. IL-33/ST2 signaling can also enhance the function of CD8⁺ T cells and other immune-related cells, such as eosinophils and polarized T cells, induce the microenvironment, and support tumor regression.^24,39–43 In IL-33-deficient mice, the number of NK cells is increased, indicating that disrupting the interaction between the IL-33/ST2 signaling pathway and Treg cells can significantly increase infiltration by NK cells.⁴⁴ Different amounts of IL-33 in the microenvironment have different effects. Low levels of IL-33 lead to immune tolerance, whereas high levels of IL-33 can enhance CD8⁺ T-cell functions. It can also be used as an immune adjuvant to enhance responses to vaccination.^43,45

Treg cells in immunotherapy

Treg cells are considered important in tumor immune escape. These cells accumulate in large numbers in the TME. Different tumor types have different immunosuppressive microenvironments.^31,46 Tregs are necessary for maintaining immune homeostasis and preventing autoimmune diseases in humans. Different subsets of Treg cells are involved in different responses and are necessary to understand the molecular pathways through which Treg cells operate in order to use these different pathways and responses to promote cancer immunotherapy.^46–48

Immunotherapeutic effect of IL-10 on Treg cells

Treg cells alter the status of antitumor immune cells and affect tumor immune cell infiltration in the TME, which is a condition for tumor growth.⁴⁹ Many factors can affect the differentiation of Treg cells.^48,50 IL-10 is a multifunctional factor that regulates the growth and differentiation of B, T, NK, and Treg cells.⁵¹ Treg cells deficient in IL-10 receptors cannot maintain FOXP3 expression and have significantly downregulated expression of FOXP3-related factors, such as IFN-γ and other proinflammatory factors. These results indicate that IL-10 may act directly on Treg cells to promote their accumulation in the TME.⁵² IL-10 is an important mediator of Treg cell-related immunity and regulates antitumor immune functions via IL-35. The loss of these two cytokines is restricted by Treg cells and has different effects on the TME. IL-10 is more important in limiting effector functions and proliferation, whereas IL-35 appears to limit memory T-cell differentiation. B lymphocyte-induced maturation protein 1 (BLIMP1) is a regulator of the terminal differentiation of T and B cells. IL-10 regulates BLIMP1 directly to affect the immune capacity of Treg cells.⁵³ In addition, IL-10 can regulate the effects of other targets of Treg immunotherapy, such as Th17 differentiation and STAT3 signaling.^54,55

Therefore, IL-10 is a promising therapeutic target for Treg-based immunotherapy.

Effect of immune blockers on Treg cell immunotherapy

CTLA-4 plays a key role in T-cell-mediated immune tolerance. Blockade of CTLA-4 delays autoimmune diseases or downregulates the immunosuppressive effects of Treg cells.^56–58 Traditionally, it has been thought that CTLA-4 and B7 interact to restrict the activation of naive T cells in lymphatic organs, leading to the failure of effector T cells in the TME.⁵⁹ However, this finding conflicts with recent studies claiming that binding of B7 to CTLA-4 may not be helpful in tumor immunotherapy.⁶⁰ As a co-inhibitory molecule, CTLA-4 negatively regulates T-cell activation. Blocking CTLA-4 can enhance activated T-cell signaling to achieve tumor immunotherapy.^61,62 It seems that no single immune blocker can currently address the requirements for immunotherapy. At present, combined therapy is commonly used to control the development of cancer, such as the combination of PD-1 and CTLA-4 blockers, and the blockade of CTLA-4 and the IL15/IL15Rα complex can kill tumor cells by enhancing the activity of NK cells.⁶³ Combination therapy increases toxicity, including diarrhea, colitis, hepatitis, and endocrine diseases, and also improves therapeutic outcomes.^64,65 In addition, Treg cells can develop resistance to immune checkpoint inhibitors, which may be due to changes in the TME that reduce the efficacy of immune checkpoint inhibitors. For example, some tumors produce more antigens that enhance Treg cell function and mediate immune escape.^66,67 Thus, further improvement of potential combination therapies is needed.

Effect of Th17 cells on Treg cell immunotherapy

The balance between Th17 and Treg cells is an important factor in immune homeostasis. Th17 cells not only participate in the host defense against pathogens, but are also involved in autoimmune diseases and cancer.^68,69 Th17 cells differentiate from naive CD4⁺ T cells and secrete IL-17. Th17 cells play multiple roles in inflammation, infection, and immune balance.⁷⁰ Both Treg and Th17 cells differentiate from naive CD4⁺ T cells, but have opposite functions. Th17 cells are involved in inflammation, autoimmunity, and cancer, whereas Treg cells inhibit immune responses. Previous studies have shown that TGF-β, IL-6, and IL-1β are important factors associated with Th17 cell differentiation.⁷¹ Treg cells can express IL-10, TGF-β, and other factors.⁷² The immunosuppressive ability of Tregs is regulated by promoting or inhibiting the differentiation of Th17 cells, which play an important role in autoimmune diseases, cancer immunotherapy, and immune homeostasis.^68,73 Recent studies have shown that regulating the balance between Th17 cells and Treg cells can lead to effective treatments, such as using bone marrow mesenchymal stem cells (BMSCs) to balance Th17 and Treg cells through the FOXP3/RORγt pathway in chronic regenerative anemia.⁷⁴ An increasing number of clinical studies have focused on the effects of the Th17/Treg axis on inflammation, autoimmunity, and cancer therapy, and its role in conditions such as systemic lupus erythematosus disease.⁷⁵ The results of those studies indicated that Th17 cells are important factors in Treg immunotherapy.

Immune-associated role of IL-33/ST2 in the TME and Treg cells

Increasing evidence suggests that the IL-33/ST2 axis in Treg cells is one of the key pathways responsible for preferential accumulation of Treg cells in the TME. Proliferation-related, immunosuppression-related, and cytokine/chemokine receptor genes are upregulated in tumor-infiltrating Treg cells, suggesting that the IL-33/ST2 axis may be a potential therapeutic target for cancer immunotherapy.⁷⁶ As a negative regulator, soluble ST2 suppresses tumor growth and metastasis by inhibiting IL-33-induced angiogenesis, Th1 and Th2 immunoreactivity, macrophage infiltration, and M2 polarization. IL-33-deficient Treg cells exhibit attenuated inhibitory abilities in vivo and promote tumor regression in an ST2-independent manner.⁵ In a murine pancreatic cancer model, cancer cell-derived sST2 enhanced tumor growth by upregulating CXCL3 via IL-33/ST2L signaling in the microenvironment of pancreatic cancer. These results suggest that sST2 and CXCL3/CXCR2 could be considered as therapeutic targets.⁷⁷ Studies on IL-33 in a murine breast cancer model showed that loss of ST2 in BALB/c mice decreases tumor growth and metastasis, accompanied by increased serum levels of cytokines such as IFN-γ, TNF-β, IL-17, and IL-4.^78,79 The IL-33/ST2 signaling pathway controls complex cytokine-related pathways in the TME, with direct or indirect effects on Treg cells, such as enhancing blocking of ST2⁺ Treg cell proliferation by IFN-γ and IL-33. ST2 is constitutively expressed in Treg cells, depending on the tissue and disease type. IL-33/ST2 recruits Treg cells to the TME and activates their immunosuppressive function, supporting tumor immune escape and favoring tumor growth.⁸⁰ The interaction of other chemokine receptors on Treg cells with chemokines in tumors, such as CCR4 and CCL12, CCR4 and CCL17, CCR10 and CCL28, and CXCR4 and CXCL1, has been reported to be involved in the recruitment of Treg cells to tumors.³⁰ In esophageal squamous cell carcinoma, IL-33 stimulates CCL2 production by involving TGF-β for recruitment by Treg cells.⁸¹ For antibody-mediated killing of tumor-infiltrating Treg cells, surface molecules that are specifically expressed on tumor Treg cells or are expressed at much higher levels in tumor Treg cells than on other T cells are good targets. These markers include the aforementioned T helper cell molecules, such as CD25, CTLA-4, GITR, 4-1BB, OX-40, LAG3, TIGIT, CCR4, and CCR8.

In short, there are similarities between targeting the IL-33/ST2 axis or Treg cells. Differential molecular expression and phenotypes play a unique role in cancer immunotherapy. Immunotherapy using targeted molecules should be further investigated.

Colorectal cancer

Epigenetic reprogramming of IL-33/ST2 in the TME is an important factor in maintaining the TME. Genetic defects in IL33 have shown benefits to immune efficacy.⁵

Colorectal cancer (CRC) is a life-threatening condition. FOXP3⁺ Treg cells have been shown to play a limited and complex role in CRC through heterogeneity in both functional and genetic phenotypes.⁸² In addition, the expression of IL-33/ST2 increases the activation of FOXP3⁺ Treg cells in CRC. Tumor-infiltrating Treg cells preferentially express increased levels of ST2. The IL-33/ST2 signaling pathway is proportional to the number of tumors. Pathological analysis has shown that the increase in ST2-positive cells is related to the accumulation of Treg cells in the CRC microenvironment.^13,83,84 Interestingly, IL-33/ST2 signaling not only promotes the development of CRC but also inhibits its progression by inducing IFNG expression through NF-κB.⁸⁵ IL-33 has been shown to play dual roles in CRC; however, its exact mechanism of action remains unknown.⁸⁶

Acute myeloid leukemia

The IL-33/ST2 signaling pathway is also associated with hematologic malignancies.⁸⁷ The most common abnormality in acute myeloid leukemia (AML) is the inversion of chromosome 16, resulting in the fusion gene CBFB-MYH11.^88,89 Recent studies have shown that IL-33/ST2 is dynamically increased in CBFB-MYH11⁺ leukemia cells, promoting their survival. IL1RL1, a key transcription factor for ST2, may be an important regulator of CBFB-MYH11⁺ LSCs.⁹⁰ AML exhibits a variety of immunosuppressive activities, such as the upregulation of Treg cells and of PD-1. IL-33/ST2 signaling promotes the effects of PD-1 blockers, further improving immunotherapeutic efficacy.^91,92 PD-L1 in the TME increases FOXP3 expression and thus its immunosuppressive effects.⁹³ The combination of PD-L1 blockade and targeting of the IL-33/ST2 signaling pathway in the TME greatly reduces the infiltration of Treg cells and constitutes a potential immunotherapeutic strategy.⁹⁴ Targeting the IL-33/ST2 pathway has been explored in AML and has a robust rationale in related fields.⁹⁵

Gastric cancer

Gastric cancer (GC) is a serious disease with high morbidity and mortality rates. The IL-33/ST2 signaling pathway also plays an important role in gastric cancer progression.^96,97 Recent studies have shown that the levels of ST2, soluble ST2, and the ST2V subtype are significantly reduced in cancer tissues as compared to noncancerous tissues in GC patients. The expression of ST2 in GC tissues was found to be significantly lower than that in adjacent tissues, suggesting that reduced expression of ST2 is related to the occurrence and development of GC. Thus, ST2 may be a potential molecular marker of GC development.⁹⁸ IL-33 stimulates mast cells in the GC TME to produce IL-11, which is necessary for the growth and development of GC. Inhibition of the IL-33/ST2 signaling pathway restricts tumor growth and reduces the production and release of the mast cell-dependent macrophage attractants CSF-2, CCL-3, and IL-6. Tumor-derived IL-33 triggers a mast cell‒macrophage-dependent signaling cascade, suggesting the potential value of IL-33 in GC treatment.⁹⁹ Treg cells are also involved in the complex TME of GC. Recent studies have shown that the number of CD4⁺ FOXP3⁺ Treg cells is positively correlated with the expression of FOXM-1 and Ki-67, which are related to immunosuppression in GC.¹⁰⁰ The formation of a complex TME, including CD4⁺/CD8⁺ T cells and FOXP3⁺ Treg cells, ultimately affects the progression and survival of GC.¹⁰¹ In summary, the IL-33/ST2 signaling pathway triggers mast cells to produce IL-11, which induces the occurrence and development of GC. Gastric mast cells also produce PD-L1 to enhance the immunosuppressive ability of Treg cells. Inhibition of the IL-33/ST2 pathway may further enhance the clinical efficacy of immune checkpoint therapy for GC.

Discussion

The components of the microenvironments of different tumors are complex but closely related. The IL-33/ST2 pathway not only promotes the occurrence and development of tumors but also inhibits related activities. The regulatory effects of Treg cells are context-dependent. Different contexts are related to different regulatory functions, such as promotion of M2 macrophage differentiation, changed epigenetic reprogramming of IFN-γ, and other factors that can accelerate tumor growth. The IL-33/ST2 signaling pathway regulates Treg cell function and thus plays a role in tumor inhibition. Recent studies have shown that IL-33 induces the transformation of tumor cells into polyploid giant cells in the TME, directly or indirectly promoting tumor metastasis and development. These data suggest that IL-33 is a key driver of drug resistance in tumors.¹⁰² The IL-33/ST2 signaling pathway not only regulates a variety of immune cells but also changes the diversity of Treg cells, which is one of the important pathways causing Treg cell enrichment in the TME.^5,6,103,104 In addition to immunosuppressive Treg cells, IL-33/ST2 signaling can recruit other immune cells, such as NK and CD8⁺ T cells, to reconstruct the TME. This can block tumor angiogenesis to prevent tumors from absorbing nutrients.

Treg cells are important factors in maintaining the immune balance and accumulate in large quantities in the TME and relevant target tissues. The IL-33/ST2 signaling pathway can promote TGF-β1-mediated Treg differentiation, stimulate DCs to secrete IL-2, and selectively amplify ST2⁺ Treg cells.^9,26 An increasing number of studies have focused on the genes, functions, and phenotypes of Treg cell per se.¹⁰⁵ Previous studies have shown that ILC-2 also regulate Treg cell activity through amphiregulin. IL-33 has been reported to promote the tumor-promoting activity of ILC-2.^106,107 The functional expression of Treg cells is affected by various components of the TME, including IL-10 and Th17 cells. IL-10 regulates the proliferation and differentiation of immune-related cells and affects immune functions. IL-10 can directly regulate BLIMP1 to affect the immune function of Treg cells. The combination of IL-10 and IL-35 promotes tumor regression by affecting proliferation and differentiation. IL-10 mediates the differentiation of Th17 cells, which are important factors in immune homeostasis and are involved in immune regulation, cancer progression, and inflammation. Th17 cells enhance immunity and achieve therapeutic effects through the balance with Treg cell pathways. The functions of Th17 cells in autoimmune diseases, immune disorders, and cancers have been widely studied.

Many studies have focused on the inseparable relationship between the IL-33/ST2 signaling pathway and Treg cells. IL-33/ST2 signaling regulates various immune cells and inflammatory cytokines. It is associated with many immune system diseases by suppressing or promoting immune functions.

Blocking IL-33 and its pathway exerts antitumor effects. IL-33/ST2 signaling is not only a downstream signal for immunotherapy but also a target for tumor therapy.¹⁰⁸ There are many links between IL-33/ST2 signaling and Treg cells. Studies have focused on indirect inhibition of the TME by MDSCs or on protumor effects by increasing Treg cells by promoting IL-2 secretion.^9,109,110 IL-33/ST2 signaling promotes FOXP3 expression and enhances Treg cell function in some contexts. The IL-33/ST2 signaling pathway can also regulate other genes to enhance or inhibit the expression of related genes. In CRC, IL-33/ST2 signaling increases the activated phenotypes of FOXP3⁺ Treg cells, increases Treg cell accumulation in the TME, and impairs immune functions. However, whether FOXP3 has antitumor effects requires further investigation. In GC, tumor-derived IL-33/ST2 signaling triggers intracellular signaling cascades in mast cells and macrophages. The IL-33/ST2 signaling pathway is dynamically expressed in leukemia cells and promotes their survival. Epigenetic reprogramming is a difficult aspect of treatment that warrants further study.

The development of different treatment modalities according to different tumor backgrounds, identification of common cancer treatment targets against common backgrounds, and investigation of signaling molecules or pathways associated with key factors are still ongoing. In future studies, more associations and roles of the IL-33/ST2 signaling pathway and Treg cells in the TME are likely to be explored.

Footnotes

Authors’ Contributions

SL, LZ, XZ, JJ, GQ, and JY devised and wrote the manuscript. All authors contributed to critical revisions of the manuscript. SL and JJ contributed equally to this paper.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by National Natural Science Foundation of China (grant nos 82060034, 82100234, 32060179), Guangxi Natural Science Foundation Project (grant no. 2020GXNSFBA297004), Guangxi University Middle-aged and Young Teachers’ Basic Research Ability Improvement Project (grant no. 2020KY12014), and Independent project of Guangxi Key Laboratory of Tumor Immunity and Microenvironment Regulation (grant no. 203030302007).

ORCID iD

Jinfeng Yang

References

Sakaguchi

Asano

Itoh

Toda

. Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25): breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 1995;155:1151–64

Khattri

Cox

Yasayko

Ramsdell

. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol 2003;4:337–42

Singh

Hjort

Thorvaldson

Sandler

. Concomitant analysis of Helios and Neuropilin-1 as a marker to detect thymic derived regulatory T cells in naive mice. Sci Rep 2015;5:7767

Mayne

Williams

. Induced and natural regulatory T cells in the development of inflammatory bowel disease. Inflamm Bowel Dis 2013;19:1772–88

Hatzioannou

Banos

Sakelaropoulos

Fedonidis

Vidali

Kohne

Handler

Boon

Henriques

Koliaraki

Georgiadis

Zoidakis

Termentzi

Beyer

Chavakis

Boumpas

Tsirigos

Verginis

. An intrinsic role of IL-33 in Treg cell-mediated tumor immunoevasion. Nat Immunol 2020;21:75–85

Aimo

Migliorini

Vergaro

Franzini

Passino

Maisel

Emdin

. The IL-33/ST2 pathway, inflammation and atherosclerosis: trigger and target? Int J Cardiol 2018;267:188–92

Sakuishi

Apetoh

Sullivan

Blazar

Kuchroo

Anderson

. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J Exp Med 2010;207:2187–94

Cayrol

Girard

. Interleukin-33 (IL-33): a nuclear cytokine from the IL-1 family. Immunol Rev 2018;281:154–68

Matta

Lott

Mathews

Liu

Rosborough

Blazar

Turnquist

. IL-33 is an unconventional Alarmin that stimulates IL-2 secretion by dendritic cells to selectively expand IL-33R/ST2+ regulatory T cells. J Immunol 2014;193:4010–20

10.

Peine

Marek

Lohning

. IL-33 in T cell differentiation, function, and immune homeostasis. Trends Immunol 2016;37:321–33

11.

Molofsky

Savage

Locksley

. Interleukin-33 in tissue homeostasis, injury, and inflammation. Immunity 2015;42:1005–19

12.

Alvarez

Fritz

Piccirillo

. Pleiotropic effects of IL-33 on CD4(+) T cell differentiation and effector functions. Front Immunol 2019;10:522

13.

Pastille

Wasmer

Adamczyk

Mager

Phuong

NNT

Palmieri

Simillion

Hansen

Kasper

Schuler

Muggli

McCoy

Buer

Zlobec

Westendorf

Krebs

. The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer. Mucosal Immunol 2019;12:990–1003

14.

Yanagisawa

Takagi

Tsukamoto

Tetsuka

Tominaga

. Presence of a novel primary response gene ST2L, encoding a product highly similar to the interleukin 1 receptor type 1. FEBS Lett 1993;318:83–7

15.

Garlanda

Dinarello

Mantovani

. The interleukin-1 family: back to the future. Immunity 2013;39:1003–18

16.

Zhao

. The enigmatic processing and secretion of interleukin-33. Cell Mol Immunol 2010;7:260–2

17.

Hayakawa

Kume

Tominaga

. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation. J Biol Chem 2007;282:26369–80

18.

Shen

Liu

Zhang

. Interleukin-33 in malignancies: friends or foes? Front Immunol 2018;9:3051

19.

Zhang

Chen

Zeng

Diao

. The contradictory role of interleukin-33 in immune cells and tumor immunity. Cancer Manag Res 2020;12:7527–37

20.

Brunner

Schiechl

Falk

Schlitt

Geissler

Fichtner-Feigl

. Interleukin-33 prolongs allograft survival during chronic cardiac rejection. Transpl Int 2011;24:1027–39

21.

Griesenauer

Jiang

Yang

Zhang

Ramadan

Egbosiuba

Campa

Paczesny

. ST2/MyD88 deficiency protects mice against acute graft-versus-host disease and spares regulatory T cells. J Immunol 2019;202:3053–64

22.

Siede

Frohlich

Datsi

Hegazy

Varga

Holecska

Saito

Nakae

Lohning

. IL-33 receptor-expressing regulatory T cells are highly activated, Th2 biased and suppress CD4 T cell proliferation through IL-10 and TGFbeta release. PLoS ONE 2016;11:e0161507

23.

Overacre-Delgoffe

Chikina

Dadey

Yano

Brunazzi

Shayan

Horne

Moskovitz

Kolls

Sander

Shuai

Normolle

Kirkwood

Ferris

Delgoffe

Bruno

Workman

Vignali

DAA

. Interferon-gamma drives Treg fragility to promote anti-tumor immunity. Cell 2017;169:1130.e11–41

24.

Smithgall

Comeau

Yoon

Kaufman

Armitage

Smith

. IL-33 amplifies both Th1- and Th2-type responses through its activity on human basophils, allergen-reactive Th2 cells, iNKT and NK cells. Int Immunol 2008;20:1019–30

25.

Smith

. The biological paths of IL-1 family members IL-18 and IL-33. J Leukoc Biol 2011;89:383–92

26.

Schiering

Krausgruber

Chomka

Frohlich

Adelmann

Wohlfert

Pott

Griseri

Bollrath

Hegazy

Harrison

Owens

BMJ

Lohning

Belkaid

Fallon

Powrie

. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature 2014;513:564–8

27.

Whiteside

. FOXP3+ Treg as a therapeutic target for promoting anti-tumor immunity. Expert Opin Ther Targets 2018;22:353–63

28.

Toker

Ohashi

. Expression of costimulatory and inhibitory receptors in FoxP3(+) regulatory T cells within the tumor microenvironment: implications for combination immunotherapy approaches. Adv Cancer Res 2019;144:193–261

29.

Blackburn

Shin

Haining

Zou

Workman

Polley

Betts

Freeman

Vignali

Wherry

. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat Immunol 2009;10:29–37

30.

Tanaka

Sakaguchi

. Targeting Treg cells in cancer immunotherapy. Eur J Immunol 2019;49:1140–6

31.

Tanaka

Sakaguchi

. Regulatory T cells in cancer immunotherapy. Cell Res 2017;27:109–18

32.

Dyck

Mills

KHG

. Immune checkpoints and their inhibition in cancer and infectious diseases. Eur J Immunol 2017;47:765–79

33.

Ribatti

Vacca

. The role of microenvironment in tumor angiogenesis. Genes Nutr 2008;3:29–34

34.

Chalubinski

Wojdan

Luczak

Gorzelak

Borowiec

Gajewski

Rudnicka

Chmiela

Broncel

. IL-33 and IL-4 impair barrier functions of human vascular endothelium via different mechanisms. Vascul Pharmacol 2015;73:57–63

35.

Choi

Min

Pyun

Maeng

Park

Kim

Kwon

. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood 2009;114:3117–26

36.

Zhang

Davis

Shah

Hughes

Ryan

Altomare

Pena

. IL-33 promotes growth and liver metastasis of colorectal cancer in mice by remodeling the tumor microenvironment and inducing angiogenesis. Mol Carcinog 2017;56:272–87

37.

Gao

Zhang

Bai

Dong

Gao

Shi

Xia

Zhang

. Transgenic expression of IL-33 activates CD8(+) T cells and NK cells and inhibits tumor growth and metastasis in mice. Cancer Lett 2013;335:463–71

38.

Chang

Hsiao

Wang

. ST2 Signaling in the tumor microenvironment. Adv Exp Med Biol 2020;1240:83–93

39.

Zhang

Miao

Kang

Tian

Xiao

Fang

. Interleukin-33 activates and recruits natural killer cells to inhibit pulmonary metastatic cancer development. Int J Cancer 2020;146:1421–34

40.

Bonilla

Frohlich

Senn

Kallert

Fernandez

Johnson

Kreutzfeldt

Hegazy

Schrick

Fallon

Klemenz

Nakae

Adler

Merkler

Lohning

Pinschewer

. The alarmin interleukin-33 drives protective antiviral CD8(+) T cell responses. Science 2012;335:984–9

41.

Bourgeois

Van

Samson

Diem

Barra

Roga

Gombert

Schneider

Gourdy

Girard

Herbelin

. The pro-Th2 cytokine IL-33 directly interacts with invariant NKT and NK cells to induce IFN-gamma production. Eur J Immunol 2009;39:1046–55

42.

Long

Dominguez

Qin

Chen

Fan

Zhang

Fang

Zhang

Kuzel

Zhang

. Type 2 innate lymphoid cells impede IL-33-mediated tumor suppression. J Immunol 2018;201:3456–64

43.

Gao

Wang

Yang

Zhao

Wen

Qin

Xie

Jiang

Zhang

Chen

Turnquist

Zhu

. Tumoral expression of IL-33 inhibits tumor growth and modifies the tumor microenvironment through CD8+ T and NK cells. J Immunol 2015;194:438–45

44.

Noel

Arshad

Filliol

Genet

Rauch

Lucas-Clerc

Lehuen

Girard

Piquet-Pellorce

Samson

. Ablation of interaction between IL-33 and ST2+ regulatory T cells increases immune cell-mediated hepatitis and activated NK cell liver infiltration. Am J Physiol Gastrointest Liver Physiol 2016;311:G313–123

45.

Villarreal

Wise

Walters

Reuschel

Choi

Obeng-Adjei

Yan

Morrow

Weiner

. Alarmin IL-33 acts as an immunoadjuvant to enhance antigen-specific tumor immunity. Cancer Res 2014;74:1789–800

46.

Whiteside

. Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert Opin Biol Ther 2014;14:1411–25

47.

Takeuchi

Nishikawa

. Roles of regulatory T cells in cancer immunity. Int Immunol 2016;28:401–9

48.

Chao

Savage

. Unlocking the complexities of tumor-associated regulatory T cells. J Immunol 2018;200:415–21

49.

Liu

Chikina

Deshpande

Menk

Wang

Tabib

Brunazzi

Vignali

Sun

Stolz

Lafyatis

Chen

Delgoffe

Workman

Wendell

Vignali

DAA

. Treg cells promote the SREBP1-dependent metabolic fitness of tumor-promoting macrophages via repression of CD8(+) T cell-derived interferon-gamma. Immunity 2019;51:381e6–97

50.

Overacre-Delgoffe

Vignali

DAA

. Treg fragility: a prerequisite for effective antitumor immunity. Cancer Immunol Res 2018;6:882–7

51.

Moore

de Waal Malefyt

Coffman

O’Garra

. Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 2001;19:683–765

52.

Murai

Turovskaya

Kim

Madan

Karp

Cheroutre

Kronenberg

. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat Immunol 2009;10:1178–84

53.

Sawant

Yano

Chikina

Zhang

Liao

Liu

Callahan

Sun

Tabib

Pennathur

Corry

Luketich

Lafyatis

Chen

Poholek

Bruno

Workman

Vignali

DAA

. Adaptive plasticity of IL-10(+) and IL-35(+) Treg cells cooperatively promotes tumor T cell exhaustion. Nat Immunol 2019;20:724–35

54.

Diefenhardt

Nosko

Kluger

Richter

Wegscheid

Kobayashi

Tiegs

Huber

Flavell

Stahl

RAK

Steinmetz

. IL-10 receptor signaling empowers regulatory T cells to control Th17 responses and protect from GN. J Am Soc Nephrol 2018;29:1825–37

55.

Hsu

Santner-Nanan

Skarratt

Lee

Stormon

Wong

Fuller

Nanan

. IL-10 Potentiates differentiation of human induced regulatory T cells via STAT3 and Foxo1. J Immunol 2015;195:3665–74

56.

Wing

Onishi

Prieto-Martin

Yamaguchi

Miyara

Fehervari

Nomura

Sakaguchi

. CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008;322:271–5

57.

Takahashi

Tagami

Yamazaki

Uede

Shimizu

Sakaguchi

Mak

Sakaguchi

. Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J Exp Med 2000;192:303–10

58.

Walunas

Lenschow

Bakker

Linsley

Freeman

Green

Thompson

Bluestone

. CTLA-4 can function as a negative regulator of T cell activation. Immunity 1994;1:405–13

59.

Korman

Peggs

Allison

. Checkpoint blockade in cancer immunotherapy. Adv Immunol 2006;90:297–339

60.

Tang

Liu

Zhang

Devenport

Lazarski

Zhang

Wang

Hwang

Zhu

Zheng

Liu

. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018;28:416–32

61.

Chen

Flies

. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nat Rev Immunol 2013;13:227–42

62.

Kumar

Bhattacharya

Prabhakar

. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 2018;95:77–99

63.

Sanseviero

O’Brien

Karras

Shabaneh

Aksoy

Zheng

Yin

Karakousis

Amaravadi

Nam

Turk

Hammerbacher

Rubinstein

Schuchter

Mitchell

Liu

Stone

. Anti-CTLA-4 activates intratumoral NK cells and combined with IL15/IL15Ralpha complexes enhances tumor control. Cancer Immunol Res 2019;7:1371–80

64.

Spain

Diem

Larkin

. Management of toxicities of immune checkpoint inhibitors. Cancer Treat Rev 2016;44:51–60

65.

Weber

Postow

Lao

Schadendorf

. Management of adverse events following treatment with anti-programmed death-1 agents. Oncologist 2016;21:1230–40

66.

Pitt

Vetizou

Daillere

Roberti

Yamazaki

Routy

Lepage

Boneca

Chamaillard

Kroemer

Zitvogel

. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and -extrinsic factors. Immunity 2016;44:1255–69

67.

Saleh

Elkord

. Treg-mediated acquired resistance to immune checkpoint inhibitors. Cancer Lett 2019;457:168–79

68.

Knochelmann

Dwyer

Bailey

Amaya

Elston

Mazza-McCrann

Paulos

. When worlds collide: Th17 and Treg cells in cancer and autoimmunity. Cell Mol Immunol 2018;15:458–69

69.

Zhu

Yamane

Paul

. Differentiation of effector CD4 T cell populations (*). Annu Rev Immunol 2010;28:445–89

70.

Chen

Yang

Qiao

. Understanding the regulatory roles of natural killer T cells in rheumatoid arthritis: T helper cell differentiation dependent or independent? Scand J Immunol 2016;84:197–203

71.

Mailer

Joly

Liu

Elias

Tegner

Andersson

. IL-1beta promotes Th17 differentiation by inducing alternative splicing of FOXP3. Sci Rep 2015;5:14674

72.

Noack

Miossec

. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmun Rev 2014;13:668–77

73.

Afzali

Lombardi

Lechler

Lord

. The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease. Clin Exp Immunol 2007;148:32–46

74.

Wang

Pang

Jiang

Liu

Xiao

Chen

Lan

Xiao

. In patients with chronic aplastic anemia, bone marrow-derived MSCs regulate the Treg/Th17 balance by influencing the Notch/RBP-J/FOXP3/RORgammat pathway. Sci Rep 2017;7:42488

75.

Yuliasih

Rahmawati

Putri

. Th17/Treg ratio and disease activity in systemic lupus erythematosus. Caspian J Intern Med 2019;10:65–72

76.

Son

Cho

Park

Moon

Park

Lee

Kim

Park

Lira

Mckenzie

Kim

Choi

Lim

Park

Kim

Park

Shin

Lee

. Tumor-infiltrating regulatory T-cell accumulation in the tumor microenvironment is mediated by IL33/ST2 signaling. Cancer Immunol Res 2020;8:1393–406

77.

Takenaga

Akimoto

Koshikawa

Nagase

. Cancer cell-derived interleukin-33 decoy receptor sST2 enhances orthotopic tumor growth in a murine pancreatic cancer model. PLoS ONE 2020;15:e0232230

78.

Jovanovic

Radosavljevic

Mitrovic

Juranic

McKenzie

Arsenijevic

Jonjic

Lukic

. ST2 deletion enhances innate and acquired immunity to murine mammary carcinoma. Eur J Immunol 2011;41:1902–12

79.

Jovanovic

Pejnovic

Radosavljevic

Pantic

Milovanovic

Arsenijevic

Lukic

. Interleukin-33/ST2 axis promotes breast cancer growth and metastases by facilitating intratumoral accumulation of immunosuppressive and innate lymphoid cells. Int J Cancer 2014;134:1669–82

80.

Choi

Sosman

Zhang

. The Janus face of IL-33 signaling in tumor development and immune escape. Cancers 2021;13:3281

81.

Yue

Lian

Wang

Luo

Yuan

Qin

Zhang

. Interleukin-33-nuclear factor-kappaB-CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells. Cancer Sci 2020;111:795–806

82.

Zhuo

Ying

Huang

Cai

. FOXP3+ Tregs: heterogeneous phenotypes and conflicting impacts on survival outcomes in patients with colorectal cancer. Immunol Res 2015;61:338–47

83.

Hua

Yuan

Zheng

Cui

Pang

Zhang

Goll

Cui

. Accumulation of FoxP3+ T regulatory cells in the tumor microenvironment of human colorectal adenomas. Pathol Res Pract 2016;212:106–12

84.

Cui

Yuan

Goll

Florholmen

. ST2 and regulatory T cells in the colorectal adenoma/carcinoma microenvironment: implications for diseases progression and prognosis. Sci Rep 2020;10:5892

85.

Eissmann

Dijkstra

Wouters

Baloyan

Mouradov

Nguyen

Davalos-Salas

Putoczki

Sieber

Mariadason

Ernst

Masson

. Interleukin 33 signaling restrains sporadic colon cancer in an interferon-gamma-dependent manner. Cancer Immunol Res 2018;6:409–21

86.

Huang

Zhao

Yan

. The role of interleukins in colorectal cancer. Int J Biol Sci 2020;16:2323–39

87.

Mager

Riether

Schurch

Banz

Wasmer

Stuber

Theocharides

Xia

Saito

Nakae

Baerlocher

Manz

McCoy

Macpherson

Ochsenbein

Beutler

Krebs

. IL-33 signaling contributes to the pathogenesis of myeloproliferative neoplasms. J Clin Invest 2015;125:2579–91

88.

Liu

Seidel

Bodine

Speck

Tarle

Collins

. Acute myeloid leukemia with Inv (16) produces a chimeric transcription factor with a myosin heavy chain tail. Cold Spring Harb Symp Quant Biol 1994;59:547–53

89.

Liu

Hajra

Wijmenga

Collins

. Molecular pathogenesis of the chromosome 16 inversion in the M4Eo subtype of acute myeloid leukemia. Blood 1995;85:2289–302

90.

Wang

Richter

Becker

Amador

Hyde

. IL1RL1 is dynamically expressed on Cbfb-MYH11(+) leukemia stem cells and promotes cell survival. Sci Rep 2019;9:1729

91.

Curran

Corrales

Kline

. Targeting the innate immune system as immunotherapy for acute myeloid leukemia. Front Oncol 2015;5:83

92.

Qin

Dominguez

Chen

Fan

Long

Zhang

Fang

Zhang

Kuzel

Zhang

. Exogenous IL-33 overcomes T cell tolerance in murine acute myeloid leukemia. Oncotarget 2016;7:61069–80

93.

Francisco

Salinas

Brown

Vanguri

Freeman

Kuchroo

Sharpe

. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J Exp Med 2009;206:3015–29

94.

Cai

Wang

Zhang

Guo

. The role of PD-1/PD-L1 axis in Treg development and function: implications for cancer immunotherapy. Onco Targets Ther 2019;12:8437–45

95.

Allegra

Innao

Tartarisco

Pioggia

Casciaro

Musolino

Gangemi

. The ST2/interleukin-33 axis in hematologic malignancies: the IL-33 paradox. Int J Mol Sci 2019;20:5226

96.

Leushacke

Tan

Wong

Swathi

Hajamohideen

Tan

Goh

Wong

Denil

SLIJ

Murakami

Barker

. Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach. Nat Cell Biol 2017;19:774–86

97.

Meyer

Goldenring

. Injury, repair, inflammation and metaplasia in the stomach. J Physiol 2018;596:3861–7

98.

Bai

You

Feng

Tao

Jiu

Nie

. Decreased ST2 expression is associated with gastric cancer progression and pathogenesis. Oncol Lett 2019;17:5761–7

99.

Eissmann

Dijkstra

Jarnicki

Phesse

Brunnberg

Poh

Etemadi

Tsantikos

Thiem

Huntington

Hibbs

Boussioutas

Grimbaldeston

Buchert

O’Donoghue

RJJ

Masson

Ernst

. IL-33-mediated mast cell activation promotes gastric cancer through macrophage mobilization. Nat Commun 2019;10:2735

100.

Liu

Zhang

Cong

Wang

Shen

Yue

. Correlations between CD4(+) FoxP3(+) Treg and expression of FoxM1 and Ki-67 in gastric cancer patients. Asia Pac J Clin Oncol 2021;17:e63–9

101.

Sun

Huang

Liu

Yuan

. CD4/CD8 + T cells, DC subsets, Foxp3, and IDO expression are predictive indictors of gastric cancer prognosis. Cancer Med 2019;8:7330–44

102.

Kudo-Saito

Miyamoto

Imazeki

Shoji

Aoki

Boku

. IL33 is a key driver of treatment resistance of cancer. Cancer Res 2020;80:1981–90

103.

Herbst

Canner

Schenkel

Smith

Kim

Hillman

Bhutkar

Cuoco

Rappazzo

Rogers

Dang

Jerby-Arnon

Rozenblatt-Rosen

Cong

Birnbaum

Regev

Jacks

. IL-33 signaling alters regulatory T cell diversity in support of tumor development. Cell Rep 2019;29:2998e8–3008

104.

Andreone

Gambardella

Mancini

Loffredo

Marcella

La Sorsa

Varricchi

Schiavoni

Mattei

. Anti-tumorigenic activities of IL-33: a mechanistic insight. Front Immunol 2020;11:571593

105.

Brown

Sadlon

Hope

Wong

Liu

Withers

Brown

Bandara

Gundsambuu

Pederson

Breen

Robertson

Forrest

Beyer

Barry

. Molecular insights into regulatory T-cell adaptation to self, environment, and host tissues: plasticity or loss of function in autoimmune disease. Front Immunol 2020;11:1269

106.

Suzuki

Leland

Joshi

Puri

. Targeting of IL-4 and IL-13 receptors for cancer therapy. Cytokine 2015;75:79–88

107.

Zaiss

van Loosdregt

Gorlani

Bekker

Grone

Sibilia

van Bergen

Henegouwen

Roovers

Coffer

Sijts

. Amphiregulin enhances regulatory T cell-suppressive function via the epidermal growth factor receptor. Immunity 2013;38:275–84

108.

Lin

Liu

. The Interleukin-33/ST2 axis promotes glioma mesenchymal transition, stemness and TMZ resistance via JNK activation. Aging 2020;12:1685–703

109.

Lim

Choi

Cho

Kim

. IL-33 inhibits the differentiation and immunosuppressive activity of granulocytic myeloid-derived suppressor cells in tumor-bearing mice. Immunol Cell Biol 2017;95:99–107

110.

Afferni

Buccione

Andreone

Galdiero

Varricchi

Marone

Mattei

Schiavoni

. The pleiotropic immunomodulatory functions of IL-33 and its implications in tumor immunity. Front Immunol 2018;9:2601