ReviewThird generation dendritic cell vaccines for tumor immunotherapy
Introduction
Among the various types of antigen presenting cells (APCs), dendritic cells (DCs) are considered to be the most potent because they can efficiently prime naïve T cells during development of T cell-mediated immunity and stimulate adaptive immune responses. Particularly, immature DCs have an exceptional ability to internalize different forms of antigen that are subsequently processed and presented within major histocompatibility complex (MHC) class I and class II molecules at the DC cell surface. However, concerns have been raised regarding the use of immature DCs (iDCs) in clinical trials since antigen presentation by iDCs, in particular antigens representing self-proteins, is known to tolerize T cells rather than immunize hosts (Schuler et al., 2003). Exposure of iDCs to danger signals in the periphery leads to their differentiation to a mature state characterized by high expression of MHC and costimulatory molecules. Therefore, upon reaching the T-cell zones of secondary lymphoid organs, mature DCs (mDCs) are well equipped to activate antigen-specific T cells. Because of these properties, mDCs generated and transfected with tumor-associated antigens (TAAs) in vitro, in a environment free of tumor-associated inhibitory factors, have evolved as a powerful vaccination tool for tumor immunotherapy. Several clinical studies using mDCs as tumor vaccines have been implemented and T cell responses were elicited against TAA epitopes derived from self-proteins (Palucka et al., 2010).
Improved understanding of the biology of DCs has revealed that three interactive signals impinge on lymphocyte responses and are important for consideration in vaccine development in order to achieve optimal activation of both innate and adaptive antitumor immunity: (i) adequate DC presentation of MHC-peptide complexes for induction of antigen-specific T cells (signal 1), with simultaneous expression of activation ligands for stimulation of innate natural killer cells; (ii) dominant positive costimulation via molecules such as CD40, CD80, and CD86 (signal 2) and (iii) secretion of cytokines that polarize immune responses in a Th1/Tc1 direction to create optimal antitumor responses (signal 3) (Fig. 1).
Section snippets
Signal 1: reproducible and efficient expression of TAAs in mDCs after transfer of in vitro transcribed RNA
One of the most commonly used strategies of antigen delivery to DCs is exogenous loading with synthetic peptides that represent defined epitopes from known TAAs (Cerundolo et al., 2004, Schuler et al., 2003, Jager et al., 2002). The short half-life of peptide-MHC complexes (pMHC) and the MHC restriction of T cell recognition that limits this approach to patients with specific MHC allotypes are major disadvantages of providing DCs with this form of antigen. Furthermore, responses directed
Signal 2: optimal costimulatory profiles are displayed by young mDCs generated in 3 days in vitro
To date, many different protocols have been described for the preparation of mDCs, which vary both with respect to the signals used for maturation and the time periods used for induction of mDC in vitro. The most common methods require around 7 days of cell culture and frequently use a maturation cocktail that was developed by Jonuleit et al. (1997), which includes TNF-α, IL-1β, IL-6 and PGE2. Dauer and colleagues demonstrated that “fast DCs” could be rapidly generated from peripheral blood
Signal 3: TLR-activated mDCs show an optimized capacity to polarize Th1/Tc1 immune responses
Analyses of Toll-like receptor (TLR)-signaling in DCs demonstrated activation of the NF-kB pathway, with resultant modulation of their cytokine secretion (reviewed in Kaisho and Tanaka, 2008). For this reason, synthetic TLR agonists are of interest for inclusion in maturation mixtures for mDCs to enable them to optimally induce antitumor responses. Many different TLRs are expressed by human monocyte-derived DCs (Ito et al., 2002). Several immunomodulatory genes are induced following ligation of
Conclusions
In our DC vaccine strategy, we utilize young mDCs that are prepared within only three days in contrast to standard procedures that utilize a 7-day culture period. Other groups are exploring the properties of fast DCs (Jarnjak-Jankovic et al., 2007, Dauer et al., 2003, Dauer et al., 2005) but we are not aware of any ongoing clinical trials at this time employing these cells. Furthermore, we developed new maturation mixtures that include synthetic TLR agonists for TLR3 and TLR7/8. We could
Acknowledgments
The authors thank the German Research Foundation (SFB-455, SFB-TR36), the European Union under the 6th Framework Programme “Allostem”, the Helmholtz Society Alliance “Immunotherapy of Cancer” and the BayImmuNet Program for financial support and the members of the laboratory for many valuable contributions to the development of DC vaccines and helpful suggestions on this manuscript. We especially thank S. Spranger for preparation of figures.
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