Concomitant Detection Of Ifn Alpha Signature And Activated Monocyte/Dendritic Cell Precursors In The Peripheral Blood Of Ifn Alpha-Treated Subjects At Early Times After Repeated Local Cytokine Treatments

Background: Interferons alpha (IFN alpha) are the cytokines most widely used in clinical medicine for the treatment of cancer and viral infections. Among the immunomodulatory activities possibly involved in their therapeutic efficacy, the importance of IFNa effects on dendritic cells (DC) differentiation and activation has been considered. Despite several studies exploiting microarray technology to characterize IFNa mechanisms of action, there is currently no consensus on the core signature of these cytokines in the peripheral blood of IFN alpha-treated individuals, as well as on the existence of blood genomic and proteomic markers of low-dose IFNa administered as a vaccine adjuvant.Methods: Gene profiling analysis with microarray was performed on PBMC isolated from melanoma patients and healthy individuals 24 hours after each repeated injection of low-dose IFNa, administered as vaccine adjuvant in two separate clinical trials. At the same time points, cytofluorimetric analysis was performed on CD14(+) monocytes, to detect the phenotypic modifications exerted by IFNa on antigen presenting cells precursors.Results: An IFNa signature was consistently observed in both clinical settings 24 hours after each repeated administration of the cytokine. The observed modulation was transient, and did not reach a steady state level refractory to further stimulations. The molecular signature observed ex vivo largely matched the one detected in CD14(+) monocytes exposed in vitro to IFNa, including the induction of CXCL10 at the transcriptional and protein level. Interestingly, IFNa ex vivo signature was paralleled by an increase in the percentage and expression of costimulatory molecules by circulating CD14(+)/CD16(+) monocytes, indicated as natural precursors of DC in response to danger signals.Conclusions: Our results provide new insights into the identification of a well defined molecular signature as biomarker of IFN alpha administered as immune adjuvants, and for the characterization of new molecular and cellular players, such as CXCL10 and CD14(+)/CD16(+) cells, mediating and possibly predicting patient response to these cytokines.