IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation

Ameri, Amir H; Tuchayi, Sara Moradi; Zaalberg, Anniek; Park, Jong Ho; Ngo, Kenneth; Li, Tiancheng; López, Elena González; Colonna, Marco; Lee, Richard T.; Mino‐Kenudson, Mari; Demehri, Shadmehr

doi:10.1073/pnas.1815016116

Cited by 64 publications

(67 citation statements)

References 23 publications

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“…This is consistent with most previous studies showing that ILC2s are increased in tumor sites [15]. Previous studies have shown that there may be a large number of pro-inflammatory cytokines such as IL-33 and IL-25 in the tumor microenvironment [44]. Pro-inflammatory cytokines can lead to activation and proliferation of ILC2s [45,46] [31][32][33].…”

Section: Discussionsupporting

confidence: 92%

ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

Wan

Huang

et al. 2020

Preprint

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Background Type 2 innate lymphoid cells (ILC2s), characterized by secreting type 2 cytokines, regulate multiple immune responses. ILC2s are found in different tumor tissues and ILC2-derived interleukin (IL)-4, IL-5, and IL-13 act on the cells in tumor microenvironment to participate in tumor progression. ILC2s are abundant in colorectal cancer (CRC) tissue, but the role of ILC2s in CRC remains unclear. Methods ILC2s were sorted from the spleen using microbeads combined with flow cytometry and tumor infiltrating CD8+ T cells were isolated from tumor tissue by microbeads. Flow cytometry and immunofluorescence were used to detect the percentage of ILC2s and CD8+ T cells in the spleen and CRC tissue. Effects of IL-9 and IL-9-stimulated CD8+ T cells on CT26 cells were measured by proliferation, apoptosis, and migration assays in vitro. GEPIA was used to detect the ILC2s chemokines in CRC tissue and adjacent normal tissue. Results We found that ILC2s were increased in CRC tissue compared with the adjacent normal tissue. In vitro experiments showed that IL-9 could activate CD8+ T cells to promote the death of CT26 cells. ILC2s were the main IL-9-secreting cells in CRC tissue as shown by flow cytometry analysis. In vivo experiments showed that neutralizing ILC2s promoted the tumor growth, while tumor inhibition occurred by intravenous injection of IL-9. Conclusions Our results demonstrated that ILC2-derived IL-9 activated CD8+ T cells to promote anti-tumor effects in CRC.

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Section: Discussionsupporting

confidence: 92%

ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

Wan

Huang

et al. 2020

Preprint

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“…Accumulating studies have demonstrated the importance of IL-33/ST2 pathway in regulating immune cell generation and function 12,15 . IL-33 can significantly enhance the recruitment of immunosuppressive immune cells into the tumor site, where these cells have a strong impact on immune microenvironment remodeling 15,17,29,51 . Exogenously administered recombinant mouse IL-33 significantly induces ST2-positive Tregs accumulated in tumor masses.…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, neutralizing IL-33 or ST2 by administration of antibodies remarkably decreases the density of ST2-positive Tregs inside tumor masses in CRC-bearing mice 63 . A more recent investigation has showed that the IL-33/Treg axis significantly contribute to the creating of tumor-promoting immune environment as seen in chronic inflammation condition 29 . Pastille E et al further revealed that Tregs in the CRC microenvironment could preferentially upregulate ST2 expression in mice.…”

Section: Discussionmentioning

confidence: 99%

ST2 and regulatory T cells in the colorectal adenoma/carcinoma microenvironment: implications for diseases progression and prognosis

Cui

Yuan

et al. 2020

Sci Rep

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ST2 (also known as IL1RL1) is the critical functional receptor for interleukin (IL)-33 in stimulating regulatory T cell (Treg) expansion and function in physiological and pathological conditions. We examined the correlation between ST2 cell expression and FoxP3 positive Tregs in both colorectal adenoma and cancer (CRC) microenvironment by real-time PCR, immunohistochemistry (IHC) and double immunofluorescences. The clinicopathological and prognostic significance of cellular ST2positive cells and FoxP3-positive Tregs in patients with adenoma and CRC were evaluated. Real-time PCR results revealed increased expression levels of ST2 and FoxP3 mRNAs in both adenoma and CRC tissues as compared with control tissues. IHC analysis confirmed increased densities of ST2-positive cells in both the adenoma/CRC epithelium and stroma, which show a close positive linear association with the densities of FoxP3-positive Tregs in respective compartments. Pathological feature analysis showed that densities of ST2-positive cells in the tumor stroma were notably associated with degree of dysplastic grading in patients with adenoma, and disease stages and lymph node metastasis in patients with CRC. Kaplan-Meier survival curves suggested that CRC patients with high densities of ST2-positive cells in the stroma tend to have a shorter overall survival. We therefore concluded that increased densities of ST2-postive cells relate to Treg accumulation within the adenoma/CRC microenvironment, suggesting the IL-33/ST2 pathway as a potential contributor for immunosuppressive milieu formation that impact disease stage and prognosis in patients with CRC. Colorectal cancer (CRC) is one of the most common malignant diseases worldwide. The progression of CRC is not only determined by CRC cells themselves but also by their immune microenvironment 1. Although high densities of immune cells have been observed in the CRC microenvironment, most CRCs still progress invasively with the development of metastasis. Most likely, these patients do not develop a satisfactory antitumor immune capacity and some CRC cells have escaped the immune surveillance control 2. Indeed, current scientific data strongly suggest that an immunosuppressive network is established in the CRC microenvironment wherein immune suppressive cells and cytokines play a critical role in inhibiting the host effective antitumor function, thereby promoting CRC progression and metastasis 3-5. Therefore, there is a great interest in studying the contributing factors of immunosuppressive microenvironment formation during CRC development 6,7. Interleukin (IL)-33, which is a member of the IL-1 cytokine family, regulates a Th2 response but also a Th1 response through natural killer cells, CD8 T cells and γδ T cells 8-11 and contributes to the generation of immunosuppressive cells 12-15. Current evidence regarding the role of IL-33 in the CRC development suggest that IL-33 is involved in the pathogenesis of CRC 1,16-18 , and IL-33 significantly promotes the establishment and progression of CRC in both...

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“…IL-33-Treg axis blockade can regulate chronic inflammation through a tumor-promoting immune environment. 61 Moreover, increased IL-33 could recruit tumor-infiltrating ST2 + Treg cells in mouse colon cancer model, 51,62 and Treg ST2KO (St2 knockout) mice had significantly increased CD8 + T cells. 61 Charlotte et al found an anti-tumorigenic role for IL-33 in colon cancer.…”

Section: Colorectal Cancermentioning

confidence: 98%

“…61 Moreover, increased IL-33 could recruit tumor-infiltrating ST2 + Treg cells in mouse colon cancer model, 51,62 and Treg ST2KO (St2 knockout) mice had significantly increased CD8 + T cells. 61 Charlotte et al found an anti-tumorigenic role for IL-33 in colon cancer. IL-33 stimulation induced the migration of colon cancer cells, which was connected with the decrease in macrophage in vitro.…”

Section: Colorectal Cancermentioning

confidence: 98%

<p>The Contradictory Role of Interleukin-33 in Immune Cells and Tumor Immunity</p>

Zhang¹,

Chen²,

Zeng³

et al. 2020

CMAR

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Interleukin (IL)-33 is a member of the IL-1 superfamily and is a crucial cytokine playing the role of a dual-function molecule. IL-33 mediates its function by interacting with its receptor suppression of tumorigenicity 2 (ST2), which is constitutively expressed on T helper (Th)1 cells, Th2 cells, and other immune cells. Previously, we summarized findings on IL-33 and performed an intensive study of the correlation between IL-33 and tumor. IL-33 enables anti-tumor immune responses through Th1 cells and natural killer (NK) cells and plays a role in tumor immune escape in cancers via Th2 cells and regulatory T cells. Herein, we discuss the contradictory role of IL-33 in immune cells in different cancer, and our summaries may be helpful for better understanding of the development of research on IL-33 and tumor immunity.

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IL-33/regulatory T cell axis triggers the development of a tumor-promoting immune environment in chronic inflammation

Cited by 64 publications

References 23 publications

ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

ILC2-derived IL-9 inhibit s colorectal cancer progression by activating CD8+ T cells

ST2 and regulatory T cells in the colorectal adenoma/carcinoma microenvironment: implications for diseases progression and prognosis

<p>The Contradictory Role of Interleukin-33 in Immune Cells and Tumor Immunity</p>

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