Integrated Expression Profiles Analysis Reveals Correlations Between the IL-33/ST2 Axis and CD8+ T Cells, Regulatory T Cells, and Myeloid-Derived Suppressor Cells in Soft Tissue Sarcoma.

Huoying Chen,Yao Chen,Yi Que,Fang Zheng,Hongbo Liu,Xing Zhang

doi:10.3389/fimmu.2018.01179

Abstract

Soft tissue sarcoma (STS) is a rare solid malignant cancer, and there are few effective treatment options for advanced disease. Cancer immunotherapy is a promising new strategy for STS treatment. IL-33 is a candidate cytokine for immunotherapy that can activate T lymphocytes and modulate antitumor immunity in some cancers. However, the expression and biological role of IL-33 in STS are poorly understood. In this study, we found that the expression of IL-33 and its receptor ST2 was decreased in STS using real-time PCR assays. By analyzing sarcoma data from The Cancer Genome Atlas, we found that higher transcriptional levels of IL-33 and ST2 were associated with a favorable outcome. There were positive correlations between the expression levels of ST2 and CD3E, CD4, CD8A, CD45RO, FOXP3, CD11B, CD33, and IFN-γ. Strong positive correlations between the expression of IFN-γ and CD3E and CD8A were also observed. Moreover, the expression levels of both IL-33 and ST2 were positively correlated with those of CD3E, CD8A, and chemokines that recruit CD8+ T cells, indicating that the IL-33/ST2 axis may play an important role in recruiting and promoting the immune response of type 1-polarized CD8+ T cells in STS. Meanwhile, we also found that the expression of IL-33 was negatively correlated with that of TGF-β1 and chemokines that recruit regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), indicating that the IL-33/ST2 axis may also contribute to antagonizing Tregs, MDSCs, and TGF-β1-mediated immunosuppression in STS. The correlations between the IL-33/ST2 axis and CD8+ T cells and IFN-γ, as well as Tregs, MDSCs, and TGF-β1 were validated by additional analyses using three other independent GEO datasets of sarcoma. Our results implicate the possible role of the IL-33/ST2 axis in modulating antitumor immunity in STS. IL-33 may not only serve as a useful prognostic biomarker for STS but also as a potential therapeutic target for STS immunotherapy and worth further investigation.

Highlights

Soft tissue sarcoma (STS) is a rare solid malignancy derived from mesenchymal tissues that accounts for approximately 1% of all cancers in adult patients [1]
By analyzing sarcoma data of TCGA and GEO, we found that the transcriptional levels of IL-33 and ST2 were positively correlated with those of CD3E, CD8A, IFN-γ, and chemokines that recruit CD8+ T cells, indicating that the IL-33/ST2 axis may play an important role in promoting the recruitment of CD8+ T cells and enhancing IFN-γ production in STS
We found that the transcriptional level of IL-33 was negatively correlated with that of TGF-β1, an immunosuppressive cytokine, and chemokines that recruit Tregs and myeloid-derived suppressor cells (MDSCs), indicating that the IL-33/ST2 axis may contribute to inhibiting the production of TGF-β1 and reducing the infiltration of Tregs and MDSCs in STS

Summary

Introduction

Soft tissue sarcoma (STS) is a rare solid malignancy derived from mesenchymal tissues that accounts for approximately 1% of all cancers in adult patients [1]. The pathogenesis of STS is poorly understood, and there are few effective treatment options for advanced disease. Despite the combination of surgery, chemotherapy, radiotherapy, and other systemic treatment, the overall 5-year survival rate of STS patients is only 50–60% [2]. Immunotherapy has emerged as a promising new treatment for cancer. Blockade of immune checkpoints has shown remarkable success in the treatment of melanoma, lung cancer, and colorectal cancer [3,4,5]. Immunotherapy offers new strategies for STS treatment. Many mechanisms responsible for the failure of antitumor immunity, including active immunosuppression by the tumor microenvironment and insufficient immune stimulatory signals, have not yet been fully elucidated in STS, which limits the development of immunotherapy for STS

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Results

Conclusion