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Review
. 2009 Dec;9(4):328-43.
doi: 10.2174/187153009789839156.

Dendritic cells for active anti-cancer immunotherapy: targeting activation pathways through genetic modification (V体育官网)

Karine Breckpot  1 , David Escors
Affiliations
Review

V体育2025版 - Dendritic cells for active anti-cancer immunotherapy: targeting activation pathways through genetic modification

Karine Breckpot et al. Endocr Metab Immune Disord Drug Targets. 2009 Dec.

Abstract

Tumour immunotherapy has become a treatment modality for cancer, harnessing the immune system to recognize and eradicate tumour cells specifically. It is based on the expression of tumour associated antigens (TAA) by the tumour cells and aims at the induction of TAA-specific effector T cell responses, whilst overruling various mechanisms that can hamper the anti-tumour immune response, e. g. regulatory T cells (Treg). (Re-) activation of effector T cells requires the completion of a carefully orchestrated series of specific steps VSports手机版. Particularly important is the provision of TAA presentation and strong stimulatory signals, delivered by co-stimulatory surface molecules and cytokines. These can only be delivered by professional antigen-presenting cells, in particular dendritic cells (DC). Therefore, DC need to be loaded with TAA and appropriately activated. It is not surprising that an extensive part of DC research has focused on the delivery of both TAA and activation signals to DC, developing a one step approach to obtain potent stimulatory DC. The simultaneous delivery of TAA and activation signals is therefore the topic of this review, emphasizing the role of DC in mediating T cell activation and how we can manipulate DC for the pill-pose of enhancing tumour immunotherapy. As we gain a better understanding of the molecular and cellular mechanisms that mediate induction of TAA-specific T cells, rational approaches for the activation of T cell responses can be developed for the treatment of cancer. .

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Figures

Fig. (1)
Fig. (1)
Anti-tumour immunity and tumour-induced suppression. In this figure, the four main mechanisms involving DC-T cell interaction in the regulation of tumour immunity are shown. (A) In an effective anti-tumour immunotherapy, mature DC (mDC) present TAA on their surface, represented as circled As. These antigens are recognised by specific CD4 and CD8 T cells in a pro-inflammatory setting (in the presence of the depicted cytokines), leading to differentiation of Th cells and CTL (T effector cells, Tef) from CD4 and CD8 T cells, respectively. (B) Antigen presentation also takes place in the tumour environment. In this setting, antigen-presenting cells such as DCreg induce antigen-specific and polyclonal tolerance leading to tumour-induced immune suppression. In the figure, a tumour-associated DCreg secretes tolerogenic cytokines IL-10 and TGF-β and converts other non-commited DC into tolerogenic DC. In an analogous manner as in A, antigens are presented to CD4 and CD8 T cells, which do not further differentiate into effector T cells. (C) Most TAA are either auto-antigens or mutated auto-antigens (quasi-auto-antigens). Therefore, natural T regulatory cells (nTreg) recognise these TAA both in the context of mature DC and immature DC (iDC) by high-affinity binding of their TCR (depicted in the picture as parallel bars between DC and nTreg). These natural Treg actively suppress DC and T effector cells by several mechanisms not yet well characterised. (D) Tumour-associated DCreg present TAA to naive and memory CD4 T cells in the context of a suppressive environment, in the presence of cytokines such as IL-10 and TGF-β, as in (B). In this situation, CD4 T cells differentiate into induced Treg (iTreg). There is increasing evidence that induced Treg can suppress immune responses in similar ways to natural Treg, as in (C).
Fig. (2)
Fig. (2)
Schematic representation of the MAPK and NF-κB pathway that are reported to enhance DC maturation. The MAPK pathway is activated upon TLR stimulation, whereas activation of the transcription factor NF-κB can be initiated by a variety of stimuli, resulting in the so-called canonical or classical pathway, initiated upon ligation of TLR, RNA helicase and PKR versus the non-classical pathway, initiated by stimuli, such as CD40L, lymphotoxin-β or RANKL. The MAPK p38 aids the binding of NF-κB to its consensus sequence by altering the chromatin structure of the DNA. Both the MAPK JNK and NF-κB pathway are important in DC maturation. They drive the expression of co-stimulatory, adhesion and antigen-presenting molecules, as well as pro-inflammatory cytokines. Moreover, NF-κB drives the expression of several feedback proteins that attenuate activation, hence avoiding chronic inflammation. One of these, the zinc finger protein A20, which has ubiquitinating and de-ubiquitinating enzymatic activity, interacts with several adaptor proteins and has been studied as a mode to mimic persistent DC activation, as such enhancing the DC’s potency to stimulate tumour antigen-specific T cells.
Fig. (3)
Fig. (3)
Targeting intracellular signalling pathways by genetic modification of DC. Gene therapy techniques allow the modification of DC function by introducing specific genes that modify intracellular signalling pathways. These signalling pathways will ultimately modify DC function by either increasing or suppressing their immunogenicity. In the figure, a viral vector carrying the therapeutic genes binds to the cell membrane (receptor recognition) and it fuses directly to the cell membrane leading to the core release. As it is the case of other vectors either based on retroviruses or not, virus-like particles can also be internalised by endocytosis. In the case of lentivectors (and other retrovirus-based vectors), through a process of reverse transcription, the therapeutic genetic information encoded as RNA is copied into a DNA version that is transported to the cell nucleus. Then, the therapeutic DNA genes are incorporated into the host genome, and they will lead to transcription and translation of both TAA and modulators of DC signalling (DC modulators). In this case, activation of ERK, JNK, p38 and NF-κB is depicted. Activation of these pathways will regulate DC maturation phenotype and cytokine secretion, and ultimately will enhance presentation of TAA to specific CD4 and CD8 T cells as shown in Fig. (1).
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