title: Epigenetic-mediated immune suppression of positive co-stimulatory molecules in chemoresistant ovarian cancer cells.
abstract: The immunological response against cancer is a critical balance between immune-activating and immune-suppressing mechanisms. Ovarian cancer creates a suppressive microenvironment to escape immune elimination; however, the molecular mechanisms are poorly understood, and it is unclear whether chemotherapeutic drugs exert an immunoreactive or immunosuppressive effect on the tumor microenvironment. 4-1BB ligand (4-1BBL/CD157) and OX-40 ligand (OX-40L/CD252) are important regulators of effector cytotoxic T-cells activity. This study demonstrates that expression of positive co-stimulatory molecules, OX-40L and 4-1BBL, is suppressed while expression of immunosuppressive molecule programmed death ligand-1 (PD-L1/CD274) is enhanced in chemoresistant cells compared to parental chemosensitive ovarian cancer cells. Here, the molecular mechanisms of silencing of OX-40L and 4-1BBL expression were investigated in chemoresistant A2780-AD ovarian cancer cells. The suppression of OX-40L and 4-1BBL are due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to gene silencing during cancer progression. We identify important epigenetic regulators, histone deacetylase 1/3 (HDAC1/HDAC3) and DNA methyltransferase 1 (DNMT1), that exhibit aberrant association with OX-40L and 4-1BBL promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increase OX-40L and 4-1BBL expression in chemoresistant cells. This study suggests that loss of histone acetylation and accumulation of DNA methylation correlates with suppressed expression of OX-40L and 4-1BBL in chemoresistant ovarian cancer cells. This study marks the first report of the regulation of these two molecules by histone deacetylation and DNA methylation in chemoresistant ovarian cancer cells.
authors.affiliation: Department of Molecular Biology Genetics, Gaziosmanpasa University, Tokat, 60250, Turkey.
authors.forename: Ercan
authors.initials: E
authors.lastname: Cacan
mesh_terms: D053330:4-1BB Ligand / Q000096:biosynthesis / Q000276:immunology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000502:physiology*; D053278:OX40 Ligand / Q000096:biosynthesis / Q000276:immunology; D010051:Ovarian Neoplasms / Q000276:immunology* / Q000378:metabolism
chemical_list: D053330:4-1BB Ligand; D000970:Antineoplastic Agents; D053278:OX40 Ligand; C089251:TNFSF4 protein, human
keywords: chemoresistance; co-stimulatory molecules; epigenetics; immune suppression; ovarian cancer