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Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting

Key Points

  • Dendritic cells (DCs) are key regulators of innate and adaptive immune responses. They are used in clinical trials to induce immune responses directed against specific antigens.

  • Clinical trials exploring DC-based vaccines mostly involve autologous DCs that are cultured and loaded with antigens ex vivo, which is a costly procedure. Targeting antigens to DC surface receptors in vivo bypasses the necessity for ex vivo DC culturing, allowing large-scale application of DC-based vaccination therapy.

  • Preclinical mouse studies for targeted delivery of antigens to DCs in vivo show successful induction of humoral and cellular responses. Targeting tumour antigens to DC surface receptors has been shown to protect mice from growing tumours and even cure them of existing tumours.

  • Strategies aimed at inducing immunity require means to mature the targeted DCs Without a proper maturation stimulus, targeted delivery of antigen might result in the induction of tolerance.

  • The specific receptor that is targeted may affect the quality of the immune response owing to differences in intracellular receptor routing, signalling pathways and expression patterns. For instance, antigens delivered to receptors preferentially expressed by the mouse CD8+ DC subset predominantly induce cellular responses, whereas antigens delivered to CD8 DC subset mainly induce humoral responses.

  • Advancing knowledge on the intracellular routing of antigen allows for the design of more potent vaccines. The use of powerful DC maturation stimuli, agents that facilitate antigen to escape from endosomes or means to prevent rapid antigen degradation have been shown to enhance humoral responses, cellular responses, or both.

Abstract

The realization that dendritic cells (DCs) orchestrate innate and adaptive immune responses has stimulated research on harnessing DCs to create more effective vaccines. Early clinical trials exploring autologous DCs that were loaded with antigens ex vivo to induce T-cell responses have provided proof of principle. Here, we discuss how direct targeting of antigens to DC surface receptors in vivo might replace laborious and expensive ex vivo culturing, and facilitate large-scale application of DC-based vaccination therapies.

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Figure 1: Intracellular fate of antigens targeted to DC surface receptors.
Figure 2: Vaccines delivering MHC class I antigens.

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Glossary

Adjuvant

An agent that does not have any specific antigenic effect in itself, but stimulates the immune system to increase the response to antigens.

Cross-presentation

The mechanism by which certain antigen-presenting cells take up, process and present extracellular antigens on MHC class I molecules to stimulate CD8+ T cells.

Immunoproteasome

The standard proteasome is composed of 14 α and β subunits, of which three, β1, β2 and β5, are involved in peptide-bond cleavage. Interferon-γ induces the expression of the immunosubunits β1i, β2i and β5i that can replace the catalytic subunits of the standard proteasome to generate the immunoproteasome, which has distinct cleavage-site preferences.

C-type lectin receptor

A receptor belonging to the family of Ca+-dependent lectins that share primary structural homology in their carbohydrate-recognition domains.

Regulatory T cell

(TReg cell). A specialized subpopulation of CD4+ T cells that suppresses immune responses to maintain tolerance to (self) antigens.

B16 melanoma model

A well-characterized model to study tumour growth in C57BL/6 mice. There are many sublines of the B16 mouse melanoma cell line, each with its own characteristics.

Hypervariable domains

Three regions within the immunoglobulin variable region that are highly divergent. Together they form a surface that is complementary to the antigen.

Framework regions

Regions adjoining the hypervariable domains, located at the N terminus of the immunoglobulin.

Humanized antibody

Genetically engineered antibody in which the hypervariable domains of a non-human antibody have been transplanted onto a human antibody.

ITAM

(Immunoreceptor tyrosine-based activation motif). A structural motif containing a tyrosine residue that is found in the cytoplasmic tails of several signalling molecules. The consensus sequence consists of Tyr-Xaa-Xaa-Leu/Ile, and the tyrosine is a target for phosphorylation by Src tyrosine kinases and subsequent binding of proteins containing SRC homologue 2 domains.

ITIM

(Immunoreceptor tyrosine-based inhibitory motif). A structural motif found in the cytoplasmic domains of many receptors that negatively regulates intracellular signalling complexes. The consensus sequence consists of Ile/Val-Xaa-Tyr-Xaa-Xaa-Leu/Val.

Toll-like receptors

(TLRs). A family of membrane-spanning proteins that recognize structurally conserved molecules that are shared by various microorganisms. Signalling through TLRs generally results in immune activation.

Single chain antibody

An antibody consisting of only one heavy and one light chain.

Poly (D,L-lactide-co-glycolide) microspheres

Biodegradable microparticles suitable for drug or antigen delivery, consisting of a polymeric ester of lactic and glycolic acid that is approved for application in humans.

Lysosomotropic

Having affinity for, and thus accumulating in, lysosomes. Lysosomotropic weak bases that are capable of crossing biological membranes selectively accumulate in acidic compartments by protonation, thereby affecting organelle pH and function.

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Tacken, P., de Vries, I., Torensma, R. et al. Dendritic-cell immunotherapy: from ex vivo loading to in vivo targeting. Nat Rev Immunol 7, 790–802 (2007). https://doi.org/10.1038/nri2173

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