The morphological variability and genetic complexity of fibroblastic sarcoma makes its diagnosis and treatment a challenge. High-mobility group box 1 protein (HMGB1), which functions as a DNA chaperone and a prototypical damage-associated molecular pattern, plays a paradoxical role in cancer. However, the expression pattern and role of HMGB1 in fibroblastic sarcomas is ill defined. By immunostaining of 95 tissue microarray cores of fibroblastic sarcomas, HMGB1 was found to be expressed in most tumor tissues. Nuclear HMGB1 translocation to cytoplasm was observed both in tumor cells and vascular endothelial cells. A visible number of tumor-associated myeloid cells including CD68+ and CD163+ macrophages and CD33+ myeloid cells were also detected in most tumor tissues. HMGB1 translocation was not only associated with CD68, CD163, and CD33 density, but also with disease progression. These results imply that HMGB1, an important regulator of the tumor microenvironment, is associated with tumor-associated myeloid cells and involved in the progression of fibroblastic sarcomas; HMGB1 may serve as a promising prognostic biomarker and a potential therapeutic target for fibroblastic sarcoma.

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.

Mesenchymal stromal cells are proven to be likely induce the angiogenic response in multiple myeloma and thus represent an enticing target for antiangiogenesis therapies for multiple myeloma. Substantial evidence indicates that angiogenesis in multiple myeloma is complex and involves direct production of angiogenic cytokines by abnormal plasma cells and these B-cell neoplasia generated pathophysiology change within the microenvironment. In this study, we demonstrated that mesenchymal stromal cells cultured with U266/Lp-1 under hypoxic conditions resulted in an increased α-smooth muscle actin expression and high productive levels of both hypoxia-inducible factor-2α and integrin-linked kinase proteins. Moreover, inhibition of hypoxia-inducible factor-2α by Small interfering RNA (siRNA) in mesenchymal stromal cells decreased the protein levels of both α-smooth muscle actin and integrin-linked kinase after mesenchymal stromal cells cultured with U266 under hypoxic conditions. We further demonstrated that transfection of integrin-linked kinase-siRNA reduced the protein level of α-smooth muscle actin and attenuated angiogenesis in vitro by decreasing the attachment of Q-dot labeled cells and secretion of angiogenic factors. In conclusion, our research showed that mesenchymal stromal cells cultured with myeloma cells under hypoxia participated in the angiogenesis of multiple myeloma, which is regulated by the hypoxia-inducible factor-2α-integrin-linked kinase pathway. Thus, targeting integrin-linked kinase may represent an effective strategy to block hypoxia-inducible factor-2α-induced angiogenesis in the treatment of multiple myeloma.

Both mesenchymal stromal cells (MSCs) and myeloid-derived suppressor cells (MDSCs) have immunosuppressive properties, and their presence may confer a worse prognosis upon cancer patients. However, whether MSCs can enhance the immunosuppressive effects of MDSCs in MM remains unknown. We evaluated the influence of MSCs on MDSCs growth, apoptosis, and functions. Our results show that MSCs promote proliferation and inhibit apoptosis in MDSCs. Additionally, MSCs enhance the ability of MDSCs by inhibiting T-cell proliferation and IFN-γ production. Furthermore, both the mRNA and protein levels of Arg1 and NOS2 were upregulated in MDSCs. These results suggest that MSCs may exert immunomodulatory effects on MDSCs by upregulating Arg1 and NOS2.