Although activation of the STAT3 pathway has been associated with tumor progression in a wide variety of cancer types (including ovarian cancer), the precise mechanism of invasion and metastasis due to STAT3 are not fully delineated in ovarian cancer. We found that pSTAT3 Tyr705 is constitutively activated in patient ascites and ascites-derived ovarian cancer cells (ADOCCs), and the range of STAT3 expression could be very high to low. In vivo transplantation of ADOCCs with high pSTAT3 expression into the ovarian bursa of mice resulted in a large primary tumor and widespread peritoneal metastases as well liver. In contrast, ADOCCs with low STAT3 expression or ADOCCs with STAT3 expression knocked down led to reduced tumor growth and an absence of metastases in vivo. Cytokines derived from the ADOCC culture medium activate the IL-6/STAT pathway in the STAT3 knockout (Ko) cells, compensating for the absence of inherent STAT3 in the cells. Treatment with HO-3867 (a novel STAT3 inhibitor at 100 ppm in an orthotopic murine model) significantly suppressed ovarian tumor growth, angiogenesis, and metastasis by targeting STAT3 and its downstream proteins. HO-3867 was found to have cytotoxic effects in ex-vivo cultures of freshly-collected human ovarian cancers, including those resistant to platinum-based chemotherapy. Our results show that STAT3 is necessary for ovarian tumor progression/metastasis and highlight the potential for targeting STAT3 by HO-3867 as a therapeutic strategy for ovarian cancer.
Purpose Oncolytic herpes simplex viruses [oHSV] represent a promising therapy for glioblastoma [GB], but their clinical success has been limited. Early innate immune responses to viral infection reduce oHSV replication, tumor destruction, and efficacy. Here, we characterized the antiviral effects of macrophages and microglia on viral therapy for GB. Experimental Design Quantitative flow cytometry of mice with intracranial gliomas [± oHSV] was utilized to examine macrophage/microglia infiltration and activation. In vitro co-culture assays of infected glioma cells with microglia/macrophages were utilized to test their impact on oHSV replication. Macrophages from TNFα knockout mice and blocking antibodies were used to evaluate the biological effects of TNFα on virus replication. TNFα blocking antibodies were utilized to evaluate the impact of TNFα on oHSV therapy in vivo. Results Flow cytometry analysis revealed a 7.9 fold increase in macrophage infiltration after virus treatment. Tumor infiltrating macrophages/microglia were polarized towards a M1, pro-inflammatory phenotype and they expressed high levels of CD86, MHCII, and Ly6C. Macrophages/microglia produced significant amounts of TNFα in response to infected glioma cells in vitro and in vivo. Utilizing TNFα blocking antibodies and macrophages derived from TNFα knockout mice we discovered TNFα induced apoptosis in infected tumor cells and inhibited virus replication. Finally, we demonstrated the transient blockade of TNFα from the tumor microenvironment with TNFα blocking antibodies significantly enhanced virus replication and survival in GB intracranial tumors. Conclusions The results of these studies suggest FDA approved TNFα inhibitors may significantly improve the efficacy of oncolytic virus therapy.
Transforming growth factor–β1 (TGF-β1) is inextricably linked to regulatory T cell (T reg ) biology. However, precisely untangling the role for TGF-β1 in T reg differentiation and function is complicated by the pleiotropic and context-dependent activity of this cytokine and the multifaceted biology of T regs . Among CD4 + T cells, T regs are the major producers of latent TGF-β1 and are uniquely able to activate this cytokine via expression of cell surface docking receptor glycoprotein A repetitions predominant (GARP) and αv integrins. Although a preponderance of evidence indicates no essential roles for T reg -derived TGF-β1 in T reg immunosuppression, TGF-β1 signaling is crucial for T reg development in the thymus and periphery. Furthermore, active TGF-β1 instructs the differentiation of other T cell subsets, including T H 17 cells. Here, we will review TGF-β1 signaling in T reg development and function and discuss knowledge gaps, future research, and the TGF-β1/T reg axis in the context of cancer immunotherapy and fibrosis.
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