title: Expression and regulation of B7-H3 immunoregulatory receptor, in human mesothelial and mesothelioma cells: immunotherapeutic implications.
abstract: No treatment prolongs the survival of malignant mesothelioma (MM) patients. Since MM elicits anti-tumor host's immune responses, immunotherapy represents a promising strategy for its control. Immunomodulatory antibodies against components of the B7 family of immunomodulatory molecules that regulate T cell activation are being investigated in human malignancies including MM. The expression of B7-H3, a new component of the B7 family was investigated in primary cultures of human mesothelial cells (HMC) and in MM cell lines by flow cytometry and molecular analyses, and in MM tissues by immunohistochemistry. The role of DNA hypomethylating agents in modulating levels of B7-H3 expression in MM cells was also studied. Reverse transcriptase-polymerase chain reaction (RT-PCR) demonstrated that B7-H3 mRNA was consistently detectable in mesothelial and MM cells investigated; however, real-time quantitative RT-PCR analyses showed highly heterogeneous levels of B7-H3 mRNA among investigated MM cells. The analysis of B7-H3 protein expression indicated that comparable levels of B7-H3 were expressed on both cell types. Treatment with the DNA hypomethylating agent 5-aza-2'-deoxycytidine did not significantly affect the expression of B7-H3 mRNA in MM cells. In vivo, while B7-H3 was expressed in all 13 tumor biopsies of the epithelial variant, with high levels in 54% of cases, it was rarely detectable in spindle type MM in which 1/5 biopsies weakly expressed B7-H3. These findings suggest that B7-H3 is a promising target for new immunotherapeutic strategies in MM, with particular emphasis in the epithelial variant.
authors.affiliation: Division of Medical Oncology and Immunotherapy, Department of Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Calabrò
authors.forename: Luca
authors.initials: L
authors.lastname: Sigalotti
authors.forename: Ester
authors.initials: E
authors.lastname: Fonsatti
authors.forename: Erica
authors.initials: E
authors.lastname: Bertocci
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Di Giacomo
authors.forename: Riccardo
authors.initials: R
authors.lastname: Danielli
authors.forename: Ornella
authors.initials: O
authors.lastname: Cutaia
authors.forename: Francesca
authors.initials: F
authors.lastname: Colizzi
authors.forename: Alessia
authors.initials: A
authors.lastname: Covre
authors.forename: Luciano
authors.initials: L
authors.lastname: Mutti
authors.forename: Pier Giorgio
authors.initials: PG
authors.lastname: Natali
authors.forename: Michele
authors.initials: M
authors.lastname: Maio
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000627:therapeutic use; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*; D060887:B7 Antigens; D019496:Cancer Vaccines / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology / Q000473:pathology; D006801:Humans; D016130:Immunophenotyping; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D009447:Neuroblastoma / Q000276:immunology / Q000473:pathology; D010996:Pleural Effusion / Q000276:immunology / Q000473:pathology; D010997:Pleural Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D060887:B7 Antigens; C423237:CD276 protein, human; D019496:Cancer Vaccines; D011971:Receptors, Immunologic