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, Hongbo Liu, Yi Que, Xing Zhang, Fang Zheng

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.