Bryostatin-1 promotes the maturation of murine and human dendritic cells and enhances the presentation of tumor-derived antigens to T cells through NF-kappa-B-dependent pathway

Abstract

Bryostatin-1 (Bryo-1) is well known for its anti-tumor activity and ability to activate T cells. In this study, we investigated the effect of Bryo-1 on dendritic cell (DC) maturation, activation, and functions. DCs were obtained from 1) murine bone marrow hematopoietic stem cells (HSC) 2) human peripheral blood monocytes and 3) Cord blood CD34+ HSC . The DCs on further stimulation with Bryo-1 + calcium ionophore (CI) induced morphologic changes and upregulation of costimulatory molecules CD40, CD80, CD86 and MHC class II, characteristic of mature DCs. Moreover, Bryo-1/CI treated DCs were able to induce a strong allo-MLR as well as exhibit enhanced tumor antigen-presenting ability to tumor-specific T cells. Such DCs induced Th1 cells by triggering the production of IFN-γ but not IL-4. Bryo-1-mediated activation of DCs involved PKC α, δ, and ι and addition of PKC inhibitors impaired allo-MLR. There was no evidence for the MAPK/ERK, p38 MAPK, or SAPK/JNK activation. Finally, Bryo-1/CI treatment induced nuclear translocation of NF-κB. Taken together, the current study suggests that Bryo-1 promotes the maturation of DCs and enhances their antigen presenting abilities to T cells. Thus, activating DCs with Bryo-1 may serve as a novel tool to enhance DC function and in the development of DC-based immunotherapy of cancer. (Supported by NIH grants R01ES09098, R21DA014885, R01HL058641, R01AI053703 and R01DA016545).