Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner

Yaqub, Sheraz; Henjum, Karen; Mahic, Milada; Jahnsen, Frode L.; Aandahl, Einar Martin; Bjørnbeth, Bjørn Atle; Taskén, Kjetil

doi:10.1007/s00262-007-0417-x

Cited by 120 publications

(115 citation statements)

References 40 publications

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“…[12][13][14] The induction of or, alternatively, the transformation to FOXP3-positive Tregs mediated by COX-2/PGE 2 has been reported, in line with the observations that adaptive Tregs on their part can suppress T-cell responses in a COX-2/PGE 2 -dependent manner. 25,26 Tregs generally are considered immunosuppressive and key mediators of peripheral tolerance. Increased levels of Tregs in the circulation and their presence in tumor tissue both are associated with poor survival in various malignancies, thus making them the focus of extensive research over the past decade.…”

Section: Discussionmentioning

confidence: 99%

Intratumoral forkhead box P3‐positive regulatory T cells predict poor survival in cyclooxygenase‐2–positive uveal melanoma

Mougiakakos

Johansson

Trocmé

et al. 2010

Cancer

104

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BACKGROUND: Forkhead box P3 (FOXP3)-positive regulatory T cells (Tregs) are key mediators of peripheral tolerance and suppress efficient antitumor responses. Prostaglandin E 2 (PGE 2 ) produced by inducible cyclooxygenase-2 (COX-2) can lead to Treg induction. COX-2 expression has been linked to tumorigenesis and growth in various malignancies. The objective of the current study was to investigate whether Tregs infiltrate uveal melanomas (UMs) and whether their prevalence is linked to COX-2 expression and the prediction of overall survival (OS). METHODS: One hundred patients who underwent enucleation after they were diagnosed with UM were included in the study. Immunohistochemical staining with monoclonal anti-FOXP3, anti-CD4, and anti-COX-2 antibodies was performed, and immunoreactivity was assessed. Correlations of COX-2 expression with the presence of Tregs, established clinicopathologic parameters, and OS were evaluated in univariate and multivariate analyses. RESULTS: High expression of COX-2 was predictive of shortened OS. FOXP3-positive Tregs were detectable in 24% of UMs and were restricted to malignant tissue. The extent of COX-2 expression was associated significantly with Treg prevalence (P ¼ .004) and Treg intratumoral localization (P ¼ .005). Intratumoral Tregs (but not the prevalence of Tregs) were independent marker for worse OS with a hazard ratio of 5.36 in patients with COX-2-positive tumors. CONCLUSIONS:The current results demonstrated that high COX-2 expression is associated with OS and Treg prevalence in UM. These findings are in line with the observations that COX-2/PGE 2 induces Tregs and that Tregs may alter antitumor responses, resulting in a negative effect on the clinical disease course. Intratumoral Tregs are an independent prognostic marker for COX

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Section: Discussionmentioning

confidence: 99%

Intratumoral forkhead box P3‐positive regulatory T cells predict poor survival in cyclooxygenase‐2–positive uveal melanoma

Mougiakakos

Johansson

Trocmé

et al. 2010

Cancer

104

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“…This indicates that Tregs may be dependent on Cox-2 to suppress anti-tumor immunity. Yaqub et al have generated some interesting results in patients with colorectal cancer [93]. Investigators found that Tregs expressed Cox-2 and produced PGE 2 .…”

Section: Cox-2 Expression and T Regulatory Cellsmentioning

confidence: 97%

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

Bernard¹,

Bancos²,

Sime³

et al. 2008

CPD

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There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastases. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

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“…IL-10, IL-8, TGF-β), prostaglandins, and VEGF, which redirect immune responses toward a favorable environment for growth [12,14,32]. Additionally, regulatory T cells (Treg) contribute to an immunosuppressive microenvironment through a cyclooxygenase-2-prostaglandin-2-dependent mechanism, direct cell-cell contact, or by the release of cytokines, like TGF-β, thereby facilitating tumor growth (see further below) [1,33,34]. Furthermore, TAMs, especially from the M2 phenotype, also release factors that favor growth and metastasis (as described above).…”

Section: Immune Escape Mechanismsmentioning

confidence: 99%

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

Deschoolmeester

Baay

Lardon

et al. 2011

Cancer Microenvironment

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There is growing evidence that both local and systemic inflammatory responses play an important role in the progression of a variety of solid tumors. Colorectal cancer (CRC) results from the cumulative effect of sequential genetic alterations, leading to the expression of tumor-associated antigens possibly inducing a cellular antitumor immune response. It is well recognized that cytotoxic lymphocytes (CTLs) constitute one of the most important effector mechanisms of anti-tumor-immunity. However, their potential prognostic influence in CRC remains controversial. In addition, other key players like natural killer cells, tumor associated macrophages and regulatory T cells play an important role in the immune attack against CRC and need further investigation. This review will mainly focus on the role of the adaptive immune system in CRC and particularly in regard to microsatellite instability.

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Regulatory T cells in colorectal cancer patients suppress anti-tumor immune activity in a COX-2 dependent manner

Cited by 120 publications

References 40 publications

Intratumoral forkhead box P3‐positive regulatory T cells predict poor survival in cyclooxygenase‐2–positive uveal melanoma

Intratumoral forkhead box P3‐positive regulatory T cells predict poor survival in cyclooxygenase‐2–positive uveal melanoma

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

Immune Cells in Colorectal Cancer: Prognostic Relevance and Role of MSI

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