Dendritic cell based vaccination strategy: an evolving paradigm

Abstract

Malignant gliomas (MG), tumors of glial origin, are the most commonly diagnosed primary intracranial malignancies in adults. Currently available treatments have provided only modest improvements in overall survival and remain limited by inevitable local recurrence, necessitating exploration of novel therapies. Among approaches being investigated, one of the leading contenders is immunotherapy, which aims to modulate immune pathways to stimulate the selective destruction of malignant cells. Dendritic cells (DCs) are potent initiators of adaptive immune responses and therefore crucial players in the development and success of immunotherapy. Clinical trials of various DC-based vaccinations have demonstrated the induction of anti-tumor immune responses and prolonged survival in the setting of many cancers. In this review, we summarize current literature regarding DCs and their role in the tumor microenvironment, their application and current clinical use in immunotherapy, current challenges limiting their efficacy in anti-cancer therapy, and future avenues for developing successful anti-tumor DC-based vaccines.

Keywords: Dendritic cell based vaccine; Glioblastoma; Immunotherapy; Malignant glioma.

Fig. 1

Demonstrating DC-T cell interaction. DCs provide three key signals to activate naïve T cells and initiate adaptive immune responses. First, DC surface p-MHC complexes are recognized by antigen-specific T cell receptors (TCRs). A second costimulatory interaction occurs between DC CD80/CD86 molecules and T cell CD28 molecules. T cells may also express CTLA-4 molecules, which interact with DC CD80/CD86 and transmit signals inhibitory to T cell activation. Depending on the presence of local cytokines, activated T cells may terminally differentiate along one of several specialized subtypes. Among these are Th1, Th2, Th17, and Treg lineages. Th1, Th2, and Th17 comprise the “activating” arms of T cell responses, and Treg cells form the “suppressive” arm. IL-12 stimulates the differentiation of Th1 cells, which produce IFN-g, an important activator of innate and adaptive immune responses. Their differentiation is inhibited by IL-4. IL-4 promotes the differentiation of Th2 cells, which secrete IL-4, IL-5, IL-6, IL-10, and IL-13, activating eosinophils, mast cells, and B cells to support humoral immunity and parasite resistance. Th2 differentiation is inhibited by IFN-g. Th17 cells develop in the presence of TGF-b and IL-6 or IL-21. They secrete IL-17, IL-17F, IL-21, and IL-22 and play key roles in the development of autoimmune tissue inflammation and resistance to infection with extracellular bacteria. The presence of TGF-b promotes the development of regulatory T cells. Suboptimal p-MHC-TCR or costimulatory interactions, which may occur through antigen presentation by immature DCs, and delivery of inhibitory signals via DC co-inhibitory molecules or CTLA-4 activation may also induce Treg cell differentiation. Treg cell development is inhibited by the IL-6. Tregs secrete IL-10 and TGF-b to suppress immune responses