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Marmonti, E.;  Oliva-Ramirez, J.;  Haymaker, C. Dendritic Cells. Encyclopedia. Available online: https://encyclopedia.pub/entry/31258 (accessed on 14 April 2024).
Marmonti E,  Oliva-Ramirez J,  Haymaker C. Dendritic Cells. Encyclopedia. Available at: https://encyclopedia.pub/entry/31258. Accessed April 14, 2024.
Marmonti, Enrica, Jacqueline Oliva-Ramirez, Cara Haymaker. "Dendritic Cells" Encyclopedia, https://encyclopedia.pub/entry/31258 (accessed April 14, 2024).
Marmonti, E.,  Oliva-Ramirez, J., & Haymaker, C. (2022, October 25). Dendritic Cells. In Encyclopedia. https://encyclopedia.pub/entry/31258
Marmonti, Enrica, et al. "Dendritic Cells." Encyclopedia. Web. 25 October, 2022.
Dendritic Cells
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Dendritic cells (DCs) are a unique myeloid cell lineage that play a central role in the priming of the adaptive immune response.  DCs are crucial sentinel cells able to recognize diverse tumor-associated antigens (TAA). Despite DCs critical “mentoring” role for T cells, single-agent DC-based therapies have been minimally successful and their combination with standard of care therapies and novel immunotherapies have shown limited improvement. The immunosuppressive tumor microenvironment (TME) is likely the main reason for this reduced efficacy. The TME significantly shapes the phenotype and function of DCs rendering them dysfunctional and tolerogenic in orchestrating an effective anti-tumor response.

antigen-presenting cells dendritic cells monocytes cancer immunotherapy

1. Distinct Origin and Development of DCs

Dendritic cells are professional antigen-presenting cells (APCs), considered central players in the orchestration and priming of both innate and adaptive immune responses against invading or threatening pathogenic agents [1][2]. Over the years, the independent origin of dendritic cells (DCs) from monocytes and macrophages has been matter of study and intense debate. In the 1990s, many groups reported the potentiality of monocytes to differentiate in vitro into DCs upon cytokine stimulation, like granulocyte/macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-α (TNFα) and IL-4 [3]. Due to their rarity in human peripheral tissue and blood, in vitro differentiation of DCs from monocytes has been a tremendously helpful tool in gaining insights into their biology. However, multiple studies have confirmed that DCs can originate from lymphoid and non-lymphoid tissues. Monocytes have been identified as precursors of peripheral non-lymphoid organ DCs and migratory DCs during inflammation, named the monocyte-derived DC (moDC) [4][5][6][7]. Therefore, until recently, monocytes have been considered progenitors of DCs, until a DC-restricted progenitor, coined the common-DC progenitor (CDP) was discovered [8].
Myeloid cells arise during hematopoiesis from hematopoietic stem cells (HSC) which are characterized by the expression of a transmembrane glycoprotein, CD34, and lacking lineage markers (Lin) [9]. Other multipotent progenitors (MMPs) or multilymphoid progenitors (MLPs) are defined as LinCD34+CD38 and can be found in bone marrow and umbilical cord blood. In the fetal liver, there is a constant ratio of CD34+CD38 stem cell and CD34+CD38+ progenitors, with abundant oligopotency activity [10]. By contrast, adult bone marrow is comprised predominantly of uni-lineage progenitors; primarily myeloid and erythroid, with an absence of oligopotent intermediates and few multipotent stem cells [10]. A recent study performed by Karamitros et al. showed that the MLP produce primarily B, NK and T cells as well as residual monocytes. The lymphoid primed multi-potential progenitor (LMPP) have lymphoid and myeloid potential in adults, but interestingly in vivo produce mainly myeloid cells [11]. In the development of the myeloid compartment, the main transcription factor (TF) is purine rich box 1 (PU.1), a family member of the erythroblast transformation specific (ETS) TF. The degree of PU.1 expression has been reported in the maturation of DCs, macrophages and neutrophils [12][13] and plays a crucial role in the gene expression of costimulatory molecules CD80, CD86 [14], OX40L [15] and fms-like tyrosine kinase 3 (Flt3) [16]. Additionally, cytokine receptor genes like IL-7Rα, M-CSFR, G-CSFR, G-MCSFRα are regulated by this TF [17].
This is distinctly different from monocyte development where, monocytes are produced by committed monocyte progenitors, GMP, monocyte-DC progenitors (MDPs), and in some cases from splenic reservoirs [18]. Downstream of the common monocyte progenitor (cMoP), a population of GMP, identified by the expression of CD123, CD45RA, CD135 (FLT3) [19], as well as expressing CLEC12Ahi and CD64hi in umbilical cord blood and bone marrow; can rise to pre-monocytes and mature monocytes [20]. In this commitment, the transcriptional factor for granulocytes development C/EBPα must be inhibited by PU.1 and interferon regulatory factor 8 (IRF8) to promote the induction of Kruppel-like factor 4 (Klf4), the main TF for monocyte differentiation [21][22][23]. The TF ReIB, a member of the NF-κB family, forms heterodimers with inhibitory proteins IkBs-like. Its inhibition can arrest monopoiesis and interstitial DCs development. Therefore, this process can induce the presence of monocyte precursor intermediates that promote the differentiation of some DC subsets [24].
Conversely DC TFs and development may change between the subpopulations. They differentiate from cDCs-precursors on based on key transcription factors, like BATF3 (Basic Leucine Zipper ATF-Like Transcription Factor 3), IRF8, ID2 (DNA binding 2), ZFBTB46 (Zinc Finger and BTB Domain Containing 46) [25][26][27][28], the growth factors FLT3L and granulocyte-macrophage colony-stimulating factor (GM-CSF) [29][30][31]. Notch and PU.1 are important transcriptional factors modulating their differentiation and maturation. Specifically, PU.1 is involved in the induction of Flt3 receptor [32] and in the discrimination of the classical DC1 (cDC1) differentiation pathway [33].

Monocytes

Interestingly, monocytes are also a heterogenous group first subdivided by Ziegler-Heitbrock et al. into 3 main subsets by the expression of CD14, a TLR-4 co-receptor for LPS, and CD16 (FcγR-III): CD14hiCD16 (classical), CD14hiCD16+ (intermediate) and CD14loCD16+ (non-classical) monocytes [34][35][36][37]. Classical monocytes represent the most abundant population comprising ~85% of total peripheral blood monocytes, show high phagocytic activity and give rise to the other monocyte subpopulations [38]. M-CSF is associated with non-classical monocytes transition; hence the blockade of this pathway depletes this population [39]. During the transition from classical to intermediate and non-classical subsets the life span expands from 1.6 days to 4.3 and 7.4 days, respectively [38]. The intermediate population is ~5% of the total monocytes in the peripheral blood and is not a homogeneous group but can be subdivided based upon the expression of the Tie2/TEK angiopoietin receptor with a ratio of 35–75% Tie2+ cells displaying angiogenic properties [40]. Recent work reported by Villani et al., confirmed the heterogeneity of this subpopulation through single cell sequencing identifying two smaller clusters within the intermediate monocyte subset named Mono3 and Mono4. The Mono3 subset expresses genes related to trafficking, cell cycle and differentiation regulation, while Mono4 is related to cytotoxic activity due to the expression of NK genes [41]. Finally, the non-classical monocyte subset is smaller in size and represents around 10% of the monocyte population in circulation and displays opposite activities compared to the classical population [35][36].
LPS stimulation of classical and non-classical monocytes showed differing behavior in the production of IL-10, IL-6, CCL2 and G-CSF with the classical subset having the highest production. Additionally, classical monocytes can express CCR2, CXCR1, CXCR2, CLEC4D and IL-13Rα1 [42]. Therefore, the principal functions of classical monocytes are related to tissue repair, phagocytosis-defense, coagulation and apoptotic clearance due to the presence of C-type lectin and scavenger receptors [43]. The intermediate population exhibit an activated phenotype with the expression of CCR5, CD11b, CD1d, CD163, MHC class II, CLEC10A, GFRa2, the highest antigen presentation, IL-2, IFNγ and ROS production [44]. Non-classical monocytes can be defined as inflammatory monocytes with the ability to produce higher amounts of TNF-α, IL-1β, have higher expression of CD115, CD294, Siglec10 and cytoskeleton rearrangement genes compared with the other subsets [42]. Thus, they are characterized by their high migratory functions, are related to immunosurveillance, endothelium transmigration and homing to lymph nodes [45].

2. DCs: The Most Potent APC of the Body

DCs are fundamental in maintaining immune homeostasis and in generating peripheral and central tolerance [46][47]. Migration through the body is a critical feature of DCs’ immunological function and maturity [48]. The migration and consequent correct localization of DCs in peripheral tissues is strictly modulated by a complex regulatory network of chemotactic, non-chemotactic signals and receptors [49][50][51]. Immature DCs (iDCs) are characterized by a lower expression of major histocompatibility complex (MHC) I and II, T cell co-stimulatory ligands (e.g, CD80, CD86, CD83), adhesion molecules and cytokines (e.g., IL-12, IL-10, and TNF) [52]. In spite of their insufficient migratory and cytokine secretory ability, iDCs are fully equipped with highly active endocytic machinery for the sampling of foreign antigens [53]. Once iDCs recognize an antigen, they start the maturation process by switching their immature endocytic activity to migratory. This program induces cytoskeletal remodeling with the consequent acquisition of a faster migratory capacity, increased expression of chemokine receptors such as CCR7 for homing and secretory capability [49][54][55][56][57][58]. In contrast, mature DCs (mDCs) reside mostly in the secondary lymphoid organs where they act as APCs through their long dendrites and multiple pseudopodia [59]. In addition, they change their phenotype throughout the gradual loss of progenitor markers like CD2, CD4, CD13, CD16, CD32 and CD33, up-regulation of adhesion molecules, costimulatory molecules and MHC on their surface. The expression of CD80, but not CD86, is the best maturation marker since it is almost absent in blood precursors and appears at more mature stages [60].
The uptake of a foreign antigen represents the triggering event of the DC maturation process. DCs interact with their microenvironment through pattern recognition receptors (PPRs), induce cytokines and internalization signaling pathways [61]. The existence of diverse DC subsets characterized by a distinct repertoire of PRRs suggests a division of labor and a specialized ability to recognize and orchestrate the stimulus-specific response [30]. In order to induce an adaptive immune response, the internalized antigen needs to be processed and presented to activate cognate naïve T cells [62]. The efficiency of antigen processing is a critical requisite for the strength of the subsequent T cell response [63]. During this immunological synapsis process, costimulatory signaling (signal 2) is one of the most important features for the correct activation of T cells. The nature of the costimulatory molecule dictates the activation and inhibition of the synapsis. This will be discussed in more detail below for individual subsets and within the tumor microenvironment.
Although an extensive description of co-stimulatory molecules has been performed; the role of inhibitory receptors in regulating DC activity is still under exploration [64]. These inhibitory pathways; also defined as immune checkpoints; are physiologically critical for maintaining self-tolerance; immune homeostasis and preventing tissue damages induced by an excessive inflammatory response [65][66]. Mapping the expression of these inhibitory receptors at steady state and upon different pathological conditions provides a better understanding of DCs functionality and novel insights into the comprehension of DC heterogeneity and therapy applications.

3. Identification of New DC Subsets

The ability to orchestrate different immune responses against a wide range of danger signals and to interact with specific T cells has been partially attributed to the presence of functionally specialized DCs subsets [30]. The DC family is a heterogeneous composition of cell types, each with a unique origin, growth factor requirement, migration pattern and immunological function [67]. In peripheral organs, they can differentiate into specific DC subtypes based upon the expression of subset-specific transcription factors [68]. The limited understanding of their phenotypic and functional heterogeneity among tissue has significantly restricted their targetability in immunotherapy [69]. Recent findings reported important differences in the expression of activator and inhibitory molecules among DCs subsets (e.g., Programmed cell dead ligand 1; PD-L1 and T cell Ig domain and mucin domain 3; Tim3), that can further bring insights in the complexity of DC heterogeneity [64].
Previously, there were no standardized guidelines for the appropriate classification of DCs into different subtypes. The low frequency of DC subsets in tissues, rarity in blood and the laborious isolation process has significantly delayed their functional characterization in humans. Initial classifications proposed were performed based upon origin (myeloid lineage or lymphoid lineage), expression of surface markers, tissue localization (migratory DCs or tissue resident DCs), maturity (iDCs or mDCs), functionality and cytokine profiles [70]. In 2008, the first attempt from a group of experts from the International Union of Immunological Societies and the World Health Organization was made to standardize the nomenclature of different DCs subtypes in the blood [35]. DCs were categorized in two subtypes: Myeloid DCs and plasmacytoid (pDCs). Myeloid DCs were further divided into CD141+ (also known as thrombomodulin) and CD1c+ (also known BDCA1) subtypes [35]. In 2014, Guilliams et al. identified four subtypes based upon ontogeny and location, function and phenotype: Classical type I DCs (cDC1s) for CD8a+ and CD103+ DCs; Classical type 2 DCs (cDC2s) for CD11b+ and CD172a+ DCs, plasmacytoid DCs (pDCs) and monocyte-derived DCs (mo-DCs) [4].
More recently, the advent of multi-color flow cytometry and mass cytometry techniques, together with advances in transcriptomic and proteomic profiling techniques, have significantly advanced our understanding of DC biology [71][72][73]. These integrated approaches have contributed to the review of the “old” classification system and the development of a “new” extended nomenclature [30][74]. The most recent refined classification system arises from Villani et al. based upon transcriptomic profiling [41]. They confirmed the earliest classification of DCs from 2014 into four main groups (cDC1, cDC2, pDC and mo-DCs), albeit with the introduction of additional levels of heterogeneity, mainly in pDCs (named DC6) and cDC2 subsets, and the identification of new populations (AS DCs, DC4). Additional transcriptomic and proteomic studies have confirmed the Villani model, although some disagreement exists regarding some new classified populations (e.g., DC4) [75][76][77][78]

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