DCs are antigen presenting cells that control immunity and tolerance. DCs are located in the surface barrier and function by recognizing pathogens in tissues within the body by examining the major histocompatibility complex (MHC) of body cells. 8 Stimulation of innate signalling receptors results in the migration of DCs to secondary lymphoid organs from the periphery. 6 This is a key factor that distinguishes DCs from macrophages, as macrophages are often sessile and remain in tissues after the initiation of inflammation. DCs are very effective antigen presenting cells and have a vital role in coordinating of both innate and adaptive immune response. 6 Therefore, high quantities of antigen are presented to DCs by cancer vaccines in order to break the tolerance. 7 DCs can be targeted very precisely by using intravenously administered RNA-lipoplexes (RNA-LPX). 5
Function of DCs and the strategies used to fight cancer (including contribution of Ralph Steinman):
In 1973, Zanvil Cohn and Ralph Steinman identified a rare cell type in the murine spleen which was identical to a phagocytic cell with dendrites like protrusions and they named them dendritic cells (DCs). Later in 1978, reports from Steinman were received that DCs were required for mixed lymphocyte reactions. During Ralph’s battle with pancreatic cancer, Ralph and his colleagues attempted to create three DC based vaccines which would improve the immune response to cancer, but were not successful and later in October 2011 Ralph Steinman passed away. 1
Mononuclear phagocytic cells are distinct ancestor of DCs which specialise in antigen presenting. DCs are able to activate T lymphocytes (capture, process, present antigen), activate B cells and are associated in the amplification of innate immune response (e.g. activation of natural killer cells). After identifying the pathogen the DCs undergo maturation which culminates with cytokine production and efficient antigen presentation. Cytokines produced than become part of the microenvironment that leads to immune responses which are capable of stimulating the development of effector T lymphocytes. 2
Vaccination strategies that involve the use of DCs have been developed. The objective of these vaccines is to induce tumour-specific effector T cells which can reduce the mass of tumour and that can lead to immunological memory to control tumour relapse. In the process of DCs vaccination the first step is to present specific tumour antigens. This can be done either by culturing ex vivo DCs that are obtained from a patient with adjuvant (that leads to DC maturation) and the specific tumour antigens and then the injection of these cells back into the patient or by inducing of DCs to take up specific tumour antigens in vivo. 3
Structure of DCs (including antigen presenting to T cells):
As shown in figure 1, dendritic cells are often rounded with reinform nuclei and a few or sometimes no dendrites.
They can initiate adaptive immune response by presenting
Pathogenic antigens to B or T lymphocytes. Figure 1 shows
a dendritic cell presenting a foreign antigen to a
Cytotoxic T cell which than leads to a specific immune response. 4
Role of RNA-lipoplexes in Cancer Immunotherapy:
The systematic delivery of vaccine antigens into dendritic cells is faced with various technical challenges. One of the most precise and effective way to target DCs is in vivo using intravenously administered RNA-lipoplexes (RNA-LPX). The function of LPX is to protect from extracellular ribonucleases, mediate the efficient uptake of RNA and its expression of the encoded antigen (by DC population and macrophages) in various lymphoid compartment. RNA-LPX causes the release of interferon-a by macrophages and plasmacytoid dendritic cells. Thus, DC maturation in inflammatory immune mechanisms and situ reminiscent of those in the early systemic phase of viral infection are activated. RNA-LPX the encodes viral/mutant neo-antigens or endogenous self-antigens lead to strong effector and memory T cell responses and also mediate potent interferon-? dependent rejections of progressive tumours. As all the polypeptide based antigens can be encoded as RNA, RNA-LPX is an example of a universally applicable vaccine class for DC targeting and synchronized induction of highly potent adaptive plus type-I-IFN-mediated innate immune mechanisms used for cancer immunotherapy. 5
The review above demonstrates the role of dendritic cells in both innate (engulfment of pathogens) and adaptive (activation of B and T cells) immune response. Also highlighting the work of Ralph Steinman and his colleagues which contributes towards finding new strategies involving dendritic cells to fight cancer. The structure of the dendritic cell is also a key factor which contributes to the function, assisting in capturing the pathogens and displaying their MHC maker to a B or T cell. Finally, the review briefly talks about the use of intravenously administered RNA-lipoplexes for the delivery of vaccine antigens into dendritic cells which is used for cancer immunotherapy.