Cellular Based Cancer Vaccines: Type 1 Polarization of Dendritic Cells

M.      Hansen; O.      Met; I.M.      Svane; M.H.      Andersen

Abstract

Cancer vaccines designed to re-calibrate the existing host-tumour interaction, tipping the balance from tumor acceptance towards tumor control holds huge potential to complement traditional cancer therapies. In general, limited success has been achieved with vaccines composed of tumor-associated antigens introduced to dendritic cells (DCs) generated in vitro. This may in part result from suboptimal maturation of DCs leading to insufficient production of IL-12, a key driver of cellular immunity. Therefore, tremendous efforts have been put into the design of maturation cocktails that are able to induce IL-12 secreting type 1 polarized DCs mimicing pathogen-derived molecular activation of DCs. Correct timing and potential synergisms of clinical-grade toll-like receptor ligands, interferons (IFN) and CD40L enhance IL-12 production in DCs. However, cytokine exhaustion, predominant expression of tolerogenic molecules and activation-induced dendritic cell death should be avoided. Thus, compounds such as IFN-γ may initially induce immunity but later on tolerance. Maturation with PGE2 obviously promotes migration via expression of CCR7 but on the down side PGE2 limits the production of IL-12 especially following encounter with CD40L-expressing cells and furthermore, PGE2 imprints DCs for preferential interaction with tolerogenic T cells. In addition, type 1 polarized DCs matured without PGE2 also seem to be capable of migrating in vivo, although concomitant production of CCL19 seems to transiently affect in vitro migration via autocrine receptor-mediated endocytosis of CCR7. In the current review, we discuss optimal design of DC maturation focused on pre-clinical as well as clinical results from standard and polarized dendritic cell based cancer vaccines.

Keywords: Cancer vaccines, dendritic cell maturation, IFN-γ, IL-12, PGE2, Th1 polarization, toll-like receptor ligands, tumor-associated, suboptimal maturation of DCs, polarized dendritic cell