Induction of Tolerance and Immunity by Dendritic Cells: Mechanisms and Clinical Applications

Abstract

Dendritic cells (DCs) are key regulators of immune responses that operate at the interface between innate and adaptive immunity, and defects in DC functions contribute to the pathogenesis of a variety of disorders. For instance, cancer evolves in the context of limited DC activity, and some autoimmune diseases are initiated by DC-dependent antigen presentation. Thus, correcting aberrant DC functions stands out as a promising therapeutic paradigm for a variety of diseases, as demonstrated by an abundant preclinical and clinical literature accumulating over the past two decades. However, the therapeutic potential of DC-targeting approaches remains to be fully exploited in the clinic. Here, we discuss the unique features of DCs that underlie the high therapeutic potential of DC-targeting strategies and critically analyze the obstacles that have prevented the full realization of this promising paradigm.

Keywords: autoimmune disorders; cancer; dendritic cells; immunotherapy; vaccine preparation.

Figure 1

Differentiation of monocyte-derived activated vs. tolerogenic dendritic cells. Dendritic cells (DC) differentiate from DC precursors into immature DCs (iDCs) in the presence of IL-4 and GM-CSF. In the presence of a maturation signal (proinflammatory cytokines and Toll-like receptor ligands), DCs become activated and transition to a stimulatory phenotype, which subsequently leads to the induction of effector/cytotoxic T cell responses. In contrast, incubation of iDCs with different mediators or genetic modification of DCs in the absence of maturation factors can lead to the generation of tolerogenic DCs, which induce anergy, apoptosis or activation of Tregs.

Figure 2

Induction of T cell-mediated immunity or tolerance by DCs. Signal (1) Antigen presentation. Dendritic cells (DCs) can present antigens on MHC I and MHC II molecules to mediate T cell activity. Signals (2) and (3) Costimulatory molecules [belonging to the B7 and tumor necrosis factor (TNF) protein families] and soluble cytokines can provide positive signaling (green arrows and receptors) to prime T cell response. Conversely, CTLA4, cytotoxic T lymphocyte antigen 4; PD1, programmed cell death protein 1; PD-L1, programmed cell death 1 ligand 1 and TIM-3, T cell immunoglobulin and mucin-domain containing-3 and soluble factors such as IL-10 can represent suppressors of T cell activation (red arrows and receptors).

Figure 3

Design of the manufacturing of DCVAC immunotherapy for cancer and autoimmune disorders. In the manufacturing of DCVAC, monocytes are harvested from patient blood by leukapheresis. For cancer patients, monocytes are differentiated into immature DCs (iDCs) in the presence of IL-4 and GM-CSF cytokines for 6 days in a GMP facility. iDCs are subsequently incubated with tumor cell lines treated with high hydrostatic pressure to induce immunogenic cell death of the tumor cells. Finally, DCs are activated using TLR3 ligand polyI:C. Aliquots of DCVAC DC-based immunotherapy are frozen in liquid nitrogen and shipped to the treatment sites. After being thawed and diluted, DCVAC is administered subcutaneously at various treatment intervals depending on the trial design. Similarly, for DM1 patients, monocytes are differentiated into iDCs in the presence of IL-4 and GM-CSF. In contrast, tolerogenic factors (dexamethasone and VitD2) are introduced to the culture at the indicated days to induce the tolerogenic phenotype of DCs. Tolerogenic DCs are finally activated with the lipopolysaccharide analog monophosphoryl lipid A (MPLA), aiming to improve the tolerogenic properties of the DCs.