editorial dendritic cells as vaccines: key regulators of tolerance and immunity · 2019. 7. 30. ·...

EditorialDendritic Cells as Vaccines: Key Regulators ofTolerance and Immunity

Jurjen Tel,1 Daniel Benitez-Ribas,2 Edith M. Janssen,3

Evelien L. J. Smits,4 and Joannes F. M. Jacobs5

1Department of Tumor Immunology, Radboudumc, Nijmegen, Netherlands2Enfermedades Hepaticas y Digestivas (CIBER), Barcelona, Spain3Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, OH, USA4Center for Oncological Research and Laboratory of Experimental Hematology, University of Antwerp, Antwerp, Belgium5Department of Laboratory Medicine, Radboudumc, Nijmegen, Netherlands

Correspondence should be addressed to Jurjen Tel; [email protected]

Received 29 March 2016; Accepted 30 March 2016

Copyright © 2016 Jurjen Tel et al.This is an open access article distributed under theCreativeCommonsAttribution License, whichpermits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Dendritic cells (DCs) are a specialized family of professionalantigen presenting cells that serve as a bridge linking theinnate and adaptive arms of our immune system. DCssense pathogens or interact with harmless antigens or non-pathogenic bacteria thereby tightly regulating the balancebetween tolerance and immunity. Despite their indispensablerole in eliciting immune responses, DCs are a rather rare andheterogeneous type of immune cell, which differ in pheno-type and function depending on maturation status, subsets,and age as well as their localization and microenvironment.Although scarce in numbers, cultured or naturally occurringDCs have been extensively investigated in clinical trials forboth their capacity of priming antigen specific cytotoxic andhelper T cells and humoral responses and their potentialto induce immunological memory, which are capacities thatdistinct them from other, nowadays, exploited forms ofimmunotherapy.

Cancer immunotherapy has been designated the scien-tific breakthrough of the year in 2013. This has a broaderimplication for DC research in general, as DC based therapycan also be used to induce tolerance in autoimmune orimmune-based diseases or to induce or improve immunityin, for instance, virally infected individuals. In this specialissue we present two original research articles as well as fivereview papers on the therapeutic potential of the use of DC

subsets forDCbased immunotherapy in cancer, autoimmunedisorders, and infectious diseases.

In their paper “Linking CD11b+ Dendritic Cells and Nat-ural Killer TCells to Plaque Inflammation inAtherosclerosis”M. Rombouts et al. performed extensive immune profilingin mice to investigate risk factors for plaque inflammationduring atherosclerosis. They demonstrate that circulatingCD11b+ cDC and NKT cells show great potential to reflectthe inflammatory status in the atherosclerotic plaque. Thismay provide biomarkers with which atherosclerotic lesionprogression can be monitored and may provide leads forimmune cell based interventions.

J. Klarquist et al. provide an oversight of the changes inDC composition, maturation, and functionality in patientswith systemic lupus erythematosus (SLE) and mouse modelsof spontaneous SLE. Based on the similarities betweenhumanand murine DC subsets as well as their reported relevanceto disease, they suggest that mouse models provide a usefulplatform for the identification, dissection, and targeting ofthe DC intrinsic and extrinsic processes that facilitate thedevelopment, progression, and possibly a cure for SLE.

In the paper entitled “Immunity and Tolerance Inducedby Intestinal Mucosal Dendritic Cells”, J. Aliberti describesthe tolerogenic potential of DC in the digestive tract understeady-state conditions. The various DC subsets orchestrate

Hindawi Publishing CorporationMediators of InflammationVolume 2016, Article ID 5789725, 2 pageshttp://dx.doi.org/10.1155/2016/5789725

2 Mediators of Inflammation

tolerogenic responses towards commensal gut flora and theyorchestrate powerful immune responses directed againstinvading pathogens. Failure to successfully complete this taskmay result in inflammatory bowel disease, food allergy, orceliac disease. Insight into the various DC subsets in the gutand the factors that influence their function may providenovel druggable targets as a basis for novel therapies.

Immunological tolerance remains a challenge in clinicalorgan transplantation and in management of autoimmunediseases. Tol-DCs are being regarded as a powerful tool toinduce immune homeostasis in autoimmune diseases and assuch are currently explored in clinical trials. In the reviewentitled “Metabolism Is Central to Tolerogenic Dendritic CellFunction”W. J. Sim et al. provide a thorough overview of howmetabolic reprogramming of DCs drives differential cellularfunction and how this specifically contributes to pathologies.Furthermore, they describe and link tolerogenic DCs withimmunosuppressive cytokines, for example, IL-10, and howthese drive the shift in metabolism during TLR stimulation.Finally, they provide an overview on how pharmacologicalmanipulation of the DC metabolism can be exploited for thegeneration of DC vaccines.

As the field of tolerogenic DC treatments moves forward,the need has arisen for the development of standardizedprotocols for the generation and application of DCs to allowcomparison between different treatments and streamline thetime from bench to bedside. A. T. Brinke et al. outlinethe efforts of the European A FACTT (Action to Focusand Accelerate Cell Based Tolerance Inducing Therapies)network that aims to harmonize DC production protocols,functional quality control parameters, immune monitoringparameters, and therapeutic regulations in order to acceleratethe implementation of cell based tolerance inducing therapiesin the clinic.

Currently, blood DC subsets are explored for the firsttime in clinical trials for treating metastatic cancer patients.S. P. Sittig et al. probed the potential of blood DC subsetsto polarize and stimulate T cells. They specifically comparedhuman plasmacytoid DCs (pDCs), BDCA1+ myeloid DCs(mDCs), and BDCA3+ mDCs and their ability to respondto TLR ligation and prime naive CD4+ T helper cells in anallogenic antigen unspecific and autologous antigen specificfashion. Although they clearly observed differences in theactivation profile of the distinct DC subsets, all activated DCsubsets were efficient in eliciting the production of IFN-𝛾 bynaive CD4+ T helper cells. Their findings further establishall three human blood DCs, despite their differences, aspromising candidates for immunostimulatory effectors incancer immunotherapy.

In the review “Pathogen-Associated Molecular PatternsInduced Crosstalk between Dendritic Cells, T Helper Cells,and Natural Killer Helper Cells Can Improve Dendritic CellVaccination,” T. Oth et al. describe the optimization of exvivo generated DC vaccines by using rationally designedcombinations of interferon gamma and different pathogen-associated molecular patterns for maturation. In this way, acellular interplay is stimulated between key players of theantitumor response, DC, T helper 1 cells, natural killer cells,and cytotoxic T cells. Activation of multiple effector cell

types might be the key to curative cancer vaccination. Inthis regard, interleukin 12-p70 is an important factor thatstimulates efficient immunity. Attention should be paid to thegeneration procedure of the cellular vaccine so that the DCwill still be able to produce interleukin 12 following injection.The outcome of DC vaccination might probably be furtherenhanced by making it part of a combination therapy thatcombines immune activationwith attacking the immunosup-pressive tumor microenvironment.

In summary, this special issue illustrates the functionof various DC subsets and their contribution to tissuehomeostasis. A better comprehension of the DC subsets andthe networks they operate on may provide novel biomarkersto diagnose, prognosticate, and monitor disease. In addition,itmay provide insights into improving the effectiveness ofDCbased immunotherapy.

Jurjen TelDaniel Benitez-Ribas

Edith M. JanssenEvelien L. J. Smits

Joannes F. M. Jacobs

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