Immature and Aberrant Phenotype of Dendritic Cells (DC) in Patients with Early Breast Cancer and significantly increased expression of CD80 and ICAMI in Healthy BRCA1 Mutant Carriers.

Background: Investigations originating from our laboratory have reported deficiencies in antigen presentation and functionality of monocytes derived from patients with early breast cancer (EBC), but not from healthy women with germline mutations of BRCA1. We have now expanded our investigations to dendritic cells (DC) which have been only insufficiently studied in patients with EBC in general and in healthy BRCA1 mutant carriers in particular. Methods: DC derived from patients with EBC and healthy women with BRCA1 mutations were analysed for the expression of DC-specific antigens CD1a, CD11c, CD83, CD80, CD86, CD54 and CD14 and of T cell-associated costimulatory molecules CD28 and CD152 (CTLA4). Antigen presentation by DCs was evaluated by a T-cell proliferation assay using tetanus toxoid (TT) as antigen. Peripheral blood was obtained from 36 patients with EBC, 5 healthy women with germline mutations of BRCA1 and from 26 healthy age-matched control persons. PBMC were prepared for ex vivo DC generation using GM-CSE IL4 and TNF-_ according to standard procedures. DC phenotype was examined by flow cytometry. T cell -- proliferation in response to TT-pulsed DCs was measured by (3H)thymidine assay. Results: DC derived from patients with EBC presented with a significantly reduced expression of DC-associated antigens CDla (p = 0.02), CD83 (p = 0.0001), CD80 (p = 0.01), CD86 (p < 0.0001)and CD54 (p < 0.000l) as compared to DC derived from healthy control females. Moreover, CD3- CD4- CD8- DC derived from the latter patient population had an obviously aberrant expression of costimulatory molecule CD28. In contrast, no significant differences in the expression of CD1a, CD86, CD83 and CD11c, hut significantly higher expression of costimulatory molecules CD80 (p = 0.003) and CD54 (p = 0.009) was found on DCs derived from healthy women with germline mutations of BRCA1, as compared to DCs derived from healthy women. Finally, T cell-proliferation in response to TT-pulsed autologous DCs was significantly decreased in patients with EBC, as compared to healthy control individuals (p < 0.0001). Conclusions: DCs derived from patients with EBC had not only an immature and aberrant phenotype, but also functional impairment in TT presentation which was not detectable prior to the development of disease in high-risk individuals with BRCA1 germline mutation. [ABSTRACT FROM AUTHOR]