Abstract
BackgroundThe standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/paclitaxel-based chemotherapy, but the overall survival rate is poor. The purpose of this study was to investigate the therapeutic potential of chemotherapy combined with inhibition of B and T lymphocyte attenuator (BTLA) for clinical use to treat EOC.MethodsInitially, we evaluated the potential application of chemotherapy combined with anti-BTLA antibody in an animal model. We then analyzed the distribution and regulation of BTLA expression on immunocytes in vitro. Finally, we examined the correlation between BTLA expression levels in cancerous tissues and prognosis in 254 EOC cases.ResultsThe combination of chemotherapy and anti-BTLA antibody for inhibiting BTLA significantly reduced peritoneal tumor volume and extended survival in tumor-bearing mice. In addition, BTLA could be identified mostly on B lymphocytes, especially on CD19hi B cells, rather than on T lymphocytes and natural killer cells. Under regulation of interleukins 6 and 10, more BTLA+CD19hi B lymphocytes could be induced through AKT and STAT3 signaling pathways. Detectable BTLA expression in ovarian cancerous tissues was associated with worse disease-free and overall survivals of EOC patients.ConclusionsBTLA detected in cancerous tissues can predict poor outcome of EOC patients. Inhibition of BTLA combined with chemotherapy can elevate immune activation and generate potent anti-tumor effects. Thus, the combination of chemotherapy and anti-BTLA antibody may hold potential clinical application for the treatment of EOC patients.Trial registrationThe Trial Registration Number was NCT00854399.
Highlights
The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/ paclitaxel-based chemotherapy, but the overall survival rate is poor
Chemotherapy combined with B and T lymphocyte attenuator (BTLA) inhibition could generate more potent anti-tumor effects Chemotherapy plays an important role on the treatment of EOCs
To preclinically explore whether the combination of chemotherapy and BTLA inhibition has a synergistic impact on generating more potent anti-tumor effects, the mAb 6A6 was used for in vivo BTLA inhibition via variRous treatment protocols (Fig. 1a)
Summary
The standard treatment for epithelial ovarian carcinoma (EOC) is surgery followed by platinum/ paclitaxel-based chemotherapy, but the overall survival rate is poor. Tumor-associated antigens can be immunogenic at some cancer sites in early neoplasia, including epithelial ovarian carcinomas (EOCs) [1,2,3]. The neoplastic cells eventually become uncontrolled by the immune system after tumor immunogenicity editing in three phases: elimination, equilibrium, and escape [1]. One mechanism for tumor growth promotion in the escape phase is immune checkpoints [4]. Tumors can activate certain immune checkpoint pathways as a mechanism of immune resistance, against the cytotoxic effects of antigen-specific T cells. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) and programmed cell death protein 1 (PD-1) are wellknown because of promising clinical applications of the respective monoclonal Abs against them [6,7,8]
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