Potential Cytotoxicity of Lipopolysaccharide Chemotypes in Ovarian Cancer Treatment

Abstract

Ovarian cancer is the deadliest gynecological malignancy, contributing to poor overall survival rates. Our previous study suggested that lipopolysaccharide (LPS) might reduce peritoneal dissemination of ovarian cancer by enhancing cytotoxic-associated innate immunogenicity. In this study, we explored the potential cytotoxic effects of different LPS chemotypes as a novel therapeutic approach for ovarian cancer. LPS-induced chemokines are toll-like receptor 4 (TLR4)-dependent and high TLR4 levels are correlated with improved overall survival outcomes. LPS did not directly impact ovarian cancer cell proliferation. Notably, LPS chemotypes, particularly lipid A, similarly modulated chemokine expression and induced cytotoxicity of peripheral blood mononuclear cells (PBMCs) to ovarian cancer cells, highlighting the critical role of lipid A component in LPS structure. Monophosphoryl lipid A (MPLA), a detoxified derivative of LPS commonly used as a vaccine adjuvant, exhibited similar cytotoxicity of PBMC when compared to LPS and induced CCL5 and CXCL8 in PBMCs. Treatment with MPLA significantly increased survival rates in the peritoneal dissemination model of ovarian cancer, reducing tumor burden and ascites. In conclusion, detoxified lipid A derivatives, such as MPLA, appear as a promising LPS-based immunotherapeutic candidate to enhance immune cell-mediated cytotoxicity for the treatment of ovarian cancer.

Keywords

lipopolysaccharides / chemokines / peripheral blood mononuclear cells / ovarian cancer

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