Plasmacytoid dendritic cell in immunity and cancer

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Review Article

Plasmacytoid dendritic cell in immunity and cancer Dana Mitchell, Sreenivasulu Chintala, Mahua Dey

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Department of Neurosurgery, IU Simon Cancer Center, Indiana University, Indiana, USA

A R T I C LE I N FO

A B S T R A C T

Keywords: Malignant glioma Glioblastoma Plasmacytoid dendritic cell Immunosuppression Tolerance Immunotherapy

Plasmacytoid dendritic cells (pDCs) comprise a subset of dendritic cells characterized by their ability to produce large amount of type I interferon (IFN-I/α). Originally recognized for their role in modulating immune responses to viral stimulation, growing interest has been directed toward their contribution to tumorigenesis. Under normal conditions, Toll-like receptor (TLR)-activated pDCs exhibit robust IFN-α production and promote both innate and adaptive immune responses. In cancer, however, pDCs demonstrate an impaired response to TLR7/9 activation, decreased or absent IFN-α production and contribute to the establishment of an immunosuppressive tumor microenvironment. In addition to IFN-α production, pDCs can also act as antigen presenting cells (APCs) and regulate immune responses to various antigens. The significant role played by pDCs in regulating both the innate and adaptive components of the immune system makes them a critical player in cancer immunology. In this review, we discuss the development and function of pDCs as well as their role in innate and adaptive immunity. Finally, we summarize pDC contribution to cancer pathogenesis, with a special focus on primary malignant brain tumor, their significance in the era of immunotherapy and suggest potential strategies for pDCtargeted therapy.

1. Introduction The role of the immune system in reacting to tumor tissue has been described as early as the eighteenth century (Parish, 2003), however cancer immunotherapy as a potentially viable field of its own, did not come into existence until the 1960s. With a deeper understanding of T cell and antigen presenting cell (APC) biology, as well as the discovery of tumor associated antigens, over the past several years cancer immunotherapy has emerged as one of the most promising avenues in the treatment of cancer, including primary malignant brain tumors (malignant gliomas). Malignant gliomas (MG) are highly aggressive, incurable tumors of glial origin and carry dismal prognosis for patients suffering from this disease (Tivnan et al., 2017). The goal of cancer immunotherapy is to overcome tumor-induced immunosuppression and augment an individual's own anti-tumor immune response using various strategies such as adoptive T cell transfer, vaccination using tumor specific peptides or tumor pulsed dendritic cells (DC), oncolytic virotherapy and immune checkpoint inhibitors (Tivnan et al., 2017). DCs are professional antigen presenting cells (APCs) and play a critical, decisive role in determining the final outcome of the immune response to antigens. Broadly, DCs can be classified into two subsets: myeloid DCs (mDCs) or classical DCs (cDCs) and plasmacytoid DCs (pDCs). This, however, is an oversimplification, as cDCs and pDCs can further be divided into subpopulations based on surface antigens,

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function and location within tissues (Collin et al., 2013; O'Keeffe et al., 2015). For the purpose of this review we will only discuss recent studies of pDC sub-classification. A thorough review of DC subsets can be found in Collin et al., 2013 and O'Keeffe et al., 2015. Recently, several studies have demonstrated that pDCs can further be divided into subsets. Alculumbre et al., demonstrated that activated pDCs could be separated into three subpopulations based on CD80 and PD-L1 expression following stimulation by a single stimulus; P1-pDCs (PD-L1+, CD80−), P2-pDCs (PD-L1+, CD80+), and P3-pDCs (PD-L1−, CD80+) (Alculumbre et al., 2018). High levels of PD-L1 expression by pDCs (P1-pDC) were found to be a marker for interferon production, which suggests an immunogenic, not tolerogenic, function for the P1pDC subset (Alculumbre et al., 2018). Villani et al., also isolated a unique subset of DCs, AS DCs, which are able to stimulate T cell proliferation and are morphologically similar to cDCs, but express pDC markers, CD123 and CD303 (Villani et al., 2017). Further supporting this finding, See et al., recently distinguished pre-DCs from pDCs and demonstrated that these pre-DCs, which express pDC markers (CD123, CD303, CD304), were able to induce proliferation and polarization of naïve CD4 T cells, whereas “pure” pDCs could not (See et al., 2017). pDCs were initially recognized as important regulators of immune responses to viral infections due to their ability to produce large amounts of IFN-α in response to viral pathogens (Megjugorac et al., 2004). Upon activation of Toll-like receptors 7 or 9 (TLR7/9) by viral

Corresponding author at: Indiana University Purdue University Indianapolis (IUPUI), Neuroscience Research Building, 320 W 15th Street, NB 400A, Indianapolis, IN 46202, USA. E-mail address: [email protected] (M. Dey).

https://doi.org/10.1016/j.jneuroim.2018.06.012 Received 22 February 2018; Received in revised form 29 May 2018; Accepted 25 June 2018 0165-5728/ © 2018 Elsevier B.V. All rights reserved.

Please cite this article as: Mitchell, D., Journal of Neuroimmunology (2018), https://doi.org/10.1016/j.jneuroim.2018.06.012

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(Asselin-Paturel et al., 2001; Blasius and Beutler, 2010; Blasius et al., 2006a; Blasius et al., 2006b). Both DC subsets arise from the same progenitor hematopoietic stem cell. It has been suggested that both common myeloid (CMP) and common lymphoid progenitors (CLP) can give rise to pDCs via an intermediate common DC progenitor (CDP), characterized by the surface phenotype Lin- CD115 + CD117+ CD135+ (Chicha et al., 2004; Naik et al., 2007). Schlitzer et al. demonstrated the existence of an intermediate CCR9-MHCIIlow precursor that is capable of differentiation into both pDCs and mDCs (Schlitzer et al., 2011). These CCR9MHCIIlow precursors differ from the pro- and pre- DCs described by Naik et al., in that they express lineage markers B220, CD11c, CD4, CD8α and CD86 (Schlitzer et al., 2011). Additionally, Ishikawa et al. have proposed the possibility of a common DC development program that is independent of the conventional myeloid and lymphoid pathways (Ishikawa et al., 2007).

DNA or RNA, pDCs promote both innate and adaptive immune responses through induction of natural killer (NK) cell migration, macrophage and dendritic cell maturation, T cell response, antigen presentation and differentiation of antibody-producing plasma cells (Jego et al., 2003, Megjugorac et al., 2004, Tough et al., 1996). Depending on the environment and the type of stimulation, pDCs are capable of engaging either immunogenic or tolerogenic functions (Kerkmann et al., 2003; Villadangos and Young, 2008). This functional variability has posed an interesting challenge and it has been shown that cancer cells capitalize on the tolerogenic capacity of pDCs to establish an immunosuppressive tumor microenvironment (TME) and promote tumorigenesis (Aspord et al., 2013). pDC dysfunction is demonstrated in cancer by impaired IFN-α secretion and upregulation of immune checkpoint mediators (Aspord et al., 2013). Additionally, in several types of cancers, an increase in tumor-associated pDCs (TApDCs) is associated with an increase in regulatory T cells (Tregs) and decreased overall survival (Gousias et al., 2013; Labidi-Galy et al., 2012; Sisirak et al., 2013b). These findings have sparked interest in investigating pDCs as potential targets in cancer immunotherapy, either through induction of IFN-α production or ablation of their immunosuppressive mechanisms. In this review, we provide a comprehensive overview of pDCs and their immunogenic role, followed by a discussion of their contribution to cancer pathogenesis and potential therapeutic interventions for targeting their dysfunction.

2.2. Regulation of pDC development Regardless of origin, only precursors expressing CD135 (Flt3 receptor) are thought to be capable of producing pDCs (D'Amico and Wu, 2003; Karsunky et al., 2005). FLT3 and its ligand, FLT3L, act via the activation of transcription factor E2–2 in a STAT3-dependent mechanism to control the expression levels of transcription factors necessary for pDC development and function (Fig. 1) (Cisse et al., 2008; Laouar et al., 2003; Li et al., 2012). E2–2 directly binds to promoter regions of the genes responsible for encoding BDCA-2, TLR-9 and ILT-7 (CD127), and to the 5′ regions of IRF-8 and IRF-7 (Cisse et al., 2008, Li et al., 2012). The functions of TLR-9, ILT-7 and IRF-7 is discussed later in the paper, however, there is conflicting information in the literature regarding the role of IRF-8. Previously, IRF-8 was suggested to be critical for pDC development. However, Sichien et al. has recently suggested that IRF-8 plays a role in regulating pDC function, but is not required for development (Schiavoni et al., 2002; Sichien et al., 2016). Their group showed that deletion of IRF-8 resulted in pDCs with increased T cell stimulatory function and decreased IFN-I production, but it did not influence pDC development or survival (Sichien, Scott, 2016). SpiB and BCL11A, are also direct targets of E2–2. SpiB plays an important role in both pDC differentiation and survival, whereas activation of BCL11A is shown to direct CDP commitment to pDC lineage and regulate transcription of E2–2, Id2, Id3 and Mtg16 via a positive feedback loop (Ippolito et al., 2014; Karrich et al., 2012; Schotte et al., 2004). pDC development is inhibited by GM-CSF through STAT5-mediated inhibition of Irf8 and upregulation of Id2 (Esashi and Liu, 2008; Esashi et al., 2008). Id2 subsequently binds to and prevents E2–2 association with target DNA sequences. It has been suggested that a balance of GMCSF-STAT5 and Flt3L-STAT3 activation drives differentiation toward one of the two DC subsets (Li, Yang, 2012). Zeb2, a zinc finger transcription factor that interacts with Smad proteins, regulates this balance and controls the commitment to pDC or cDC lineage through Id2 expression regulation (Scott et al., 2016; Wu et al., 2016). Zeb2 also promotes the expression of M-CSFR, which may drive pDC development in a Flt3-L independent manner (Fancke et al., 2008). In addition to its role in pDC development, E2–2 may be critical in the maintenance of pDC identity. Deletion of E2–2 in pDCs is shown to result in a loss of pDC-associated cell markers and spontaneous cDC-like differentiation. While there is evidence that E2–2 directly binds to and controls the gene expression program of pDCs, it has also been suggested that E2–2 may inhibit commitment to the cDC cell fate by direct repression of cDC-associated genes (Ghosh et al., 2010).

2. pDC origin, development and regulation 2.1. Origin of pDC pDCs arise from hematopoietic stem cells in the bone marrow, are morphologically round, with a well-developed rough endoplasmic reticulum (RER) and Golgi apparatus (Ghosh et al., 2010). Upon in vitro stimulation with IL-3, pDCs are shown to assume a cDC-like morphology, mature into antigen presenting cells and acquire the ability to stimulate TH2 responses (Ghosh et al., 2010, Grouard et al., 1997). Human pDCs are identified phenotypically by the absence of CD11c, ILT-1, and leukocyte lineage markers (e.g. CD3, CD14, CD19, CD56), as well as by the presence of CD4, CD123, HLA-DR, CD68 and ILT-3 (Dzionek et al., 2001). Additionally, human pDCs are known to express ILT-7, a cell surface receptor involved in the negative modulation of IFN-α production, and BDCA-2, a C-type lectin involved in ligand internalization and inhibition of IFN-α/β synthesis (Cao et al., 2006, Dzionek et al., 2001). The expression of CD2, a surface adhesion molecule, further distinguishes two subsets of pDCs (Matsui et al., 2009). CD2hi pDCs have been shown to secrete higher levels of IL-12, express higher levels of CD80 and possess a greater capacity to initiate T cellmediated immune responses (Matsui et al., 2009). Further, Zhang et al. recently demonstrated subsets of pDCs within the CD2hi population that differ in their morphology, function and expression of CD5 and CD81. CD5 + CD81+ pDCs were shown to express more IRF-5, less IRF-7 and produce less type I interferon than CD5-CD81- pDCs (Zhang et al., 2017). These CD5 + CD81+ pDCs were also suggested to be superior in triggering T cell proliferation as well as Treg and plasma cell differentiation (Zhang et al., 2017). As discussed previously, Villani et al., recently classified these CD2 + CD5+ cells, previously thought to be pDCs, as AS DCs, which are functionally distinct from pDCs, but maintain expression of pDC markers, CD123 and CD303 (Villani et al., 2017). Additionally, Alculumbre et al., demonstrated that activated pDCs, which were subsequently classified into three subsets, arise from CD2-CD5- pDCs (Alculumbre, Saint-Andre, 2018). These findings contrast those of Zhang et al., and suggest that these CD2 + CD5+ cells may be distinct from pDCs (Alculumbre et al., 2018, Villani et al., 2017, Zhang et al., 2017). Murine pDCs, in contrast, are CD11c+, and do not express the Flt3 receptor unless treated with Flt3L. They also express cell surface antigens B220, Ly6C, BST2, mPDCA-1 and SIGLEC-H

2.3. pDC migration Following development in the bone marrow, pDCs migrate to secondary lymphoid tissues via high endothelial venules (HEV) (Cella 2

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Fig. 1. E2–2 mediated regulation of pDC development and function. FLT3 and its ligand, FLT3L, act via the activation of transcription factor E2-2 in a STAT3dependent mechanism to control the expression levels of transcription factors necessary for pDC development and function. E2-2 is inhibited by GM-CSF thorough STAT5-mediated inhibition of Irf8 and upregulation of Id2. MTG16 inhibits ID2, thereby promoting E2-2 function. Zeb2, a zinc finger transcription factor controls the commitment to pDC lineage through Id2 expression regulation and drives M-CSF mediated FLT3-independent pDC development.

negative chemokine gradient (Kohrgruber et al., 2004). In addition to CXCR3 and CXCR4, several other factors have been suggested to play a role in pDC migration. CCR7 and Chemerin mediate the homing of pDCs to lymph nodes in both homeostatic and inflammatory states, while CXCR3, CCR5 and CD2AP promote pDC migration to inflamed tissues (Albanesi et al., 2009, Diacovo et al., 2005, Krug et al., 2002, Seth et al., 2011, Srivatsan et al., 2013). CCR6 and CCR10 drive pDC migration from the tonsils to inflamed epithelium, and CCR9 is required for migration to the small intestine (Sisirak et al., 2011; Wendland et al., 2007). Lastly, DOCK2, a CDM protein known to regulate actin cytoskeleton via Rac activation, has been implicated in both pDC migration and IFN-α production (Gotoh et al., 2008, Gotoh et al., 2010).

et al., 1999; Vanbervliet et al., 2003). pDCs express high levels of CD62 (L-selectin), suggesting that trafficking of pDCs from the blood to lymphoid tissue through HEVs may be CD62L-mediated during homeostatic states (Cella, Jarrossay, 1999, Vanbervliet, Bendriss-Vermare, 2003). High expression of CCR2, CCR5, CCR7, CXCR3 and CXCR4 has also been demonstrated on pDCs (Penna et al., 2001). To date, the most appreciated mediator of pDC migration is CXCR4 (Vanbervliet et al., 2003). It was initially suggested that CXCR4 and its ligand SDF-1/CXCL12 were largely responsible for pDC migration. Recent studies, however, suggest a synergistic mechanism involving both CXCR3 and CXCR4 (Krug et al., 2002, Penna et al., 2001, Vanbervliet et al., 2003). Penna et al. demonstrated that pDCs exhibit efficient migration in response to SDF-1/CXCR12 and only negligible response to CXCR3 ligands (CXCL11). However, Krug et al. show that the presence of CXCL12 increases the response of both human and murine pDCs to CXCL11 (Krug et al., 2002, Penna et al., 2001). Consistent with the hypothesized synergism of CXCR3 and CXCR4, their ligands, CXCL12 and CXCL11, demonstrate adjacent expression in both lymphoid tissues and inflamed epithelium (Vanbervliet et al., 2003). In contrast, Kohrgruber et al. suggest that pDC migration can be mediated by a CXCR3-dependent mechanism in the absence of CXCR4-mediated chemotaxis (Kohrgruber et al., 2004). This mechanism, which is entirely independent of CXCR4, requires the immobilization of CXCR3 ligands to the apical side of endothelial cells and the generation of a

2.4. Regulation of pDC function Modulation of pDC functions have been attributed to various factors (Fig. 2) including CD336 (Schuster et al., 2010), BST2 (Cao et al., 2009), CLEC4A (Meyer-Wentrup et al., 2008), BDCA2, CD300A and C, ILT7, and LAIR1 in human, and Siglec-H, Bst2, Pdc-Trem and Ly49Q in mice (Reizis et al., 2011; Swiecki and Colonna, 2015). CD28 expression on murine pDC has been shown in the inhibition of type I interferon (e.g IFN-α) production in response to TLR engagement (Macal et al., 2016). Likewise, MYC transcription factor negatively regulates IFN-α 3

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Fig. 2. Regulation of pDC function. Several factors are shown to be important in modulating the various functions of pDCs including: CD336, BST2, CLEC4A BDCA2, CD300A and C, ILT-7, and LAIR1 in humans, and SIGLEC-H, BST2, PDC-TREM and Ly49Q in mice Studies have demonstrated several additional regulators of pDC function. CD28 expression on murine pDCs is inhibits pDC IFN-I production in response to TLR engagement. Likewise, the transcription factor MYC, negatively regulates pDC IFN-I production through the repression of IRF-7 transcription. Tim-3, a marker of activation and exhaustion, is also found to be expressed on pDCs with impaired IFN-I production (Schwartz, Clayton, 2017). In contrast, Fyn and Lyn, Src family kinases that phosphorylate ITAMs/ITIMs associated with pDC receptors, promote pDC IFN-I and pro-inflammatory cytokine production.

induction of NK cell migration and stimulation of macrophage and dendritic cells (Megjugorac, Young, 2004). Through the recruitment of IRF-5, MyD88 also activates NF-kB-induced transcription of genes encoding pro-inflammatory cytokines and chemokines (Takaoka et al., 2005). While type I IFNs are suggested to play a protective role in antiviral immunity, there is mounting evidence that chronic type I IFN secretion may result in pathologic inflammation and apoptosis (Ciancanelli et al., 2015; Davidson et al., 2014). In chronic viral infections, such as HIV, pDCs are shown to exhibit persistent IFN-α secretion and promote T cell apoptosis via the production of T cell recruiting chemokines and expression of TRAIL (Achard et al., 2017; O'Brien et al., 2011).

production through the inhibition of IRF-7 transcription. Furthermore, Tim-3, a marker of pDC dysfunction may inhibits IFN-α production through impairment of TLR signaling and recruitment of IRF7 and p85 into lysosomes, activating their degradation (Schwartz et al., 2017). In contrast, Fyn and Lyn, Src family kinases that phosphorylate ITAMs/ ITIMs associated with pDC receptors, promote pDC IFN-α and pro-inflammatory cytokine production (Dallari et al., 2017). Additionally, the PI3K and MAPK pathways have been shown to be critical regulators of pDC IFN-α production in response to TLR stimulation (Guiducci et al., 2008, Osawa et al., 2006). pDCs can also act as antigen presenting cells and constitutively express MHC-II. MHC-II is tightly regulated by transcriptional activation involving protein complex known as enhanceosome containing Regulatory factor x (RFX), cyclic AMP responsive-element-binding protein (CREB), Y-box specific nuclear transcription factor Y (NFY) and Class II major histocompatibility complex transactivator (CIITA). CIITA a master control factor that regulates the expression of MHC II, is activated and repressed by several factors including Interferon-g (IFNg), TNFα, TGFβ and IL10 (Lee et al., 1997; Muhlethaler-Mottet et al., 1998; O'Keefe et al., 1999; Steimle et al., 1994). Additionally, CIITA is post translationally modulated through the phosphorylation, ubiquitination (Greer et al., 2004; Greer et al., 2003; Sisk et al., 2003; Tosi et al., 2002). In glioma, CIITA is regulated by IFNγ (Takamura et al., 2004) TNFα (Luder et al., 2003), IL-1beta (Rohn et al., 1999), and TGFβ (Lee et al., 1997).

3.2. Adaptive immune system Through IFN-α secretion, pDCs serve to link the innate and adaptive immune systems via the induction of TH1 cell polarization (Fig. 3) (Cella et al., 2000; Facchetti et al., 2003), suppression of TH17 responses (Guo et al., 2008), promotion of CD8+ T cell survival and expansion (Tough, Borrow, 1996) and stimulation of antibody-producing plasma cell differentiation (Jego, Palucka, 2003). TLR9-activated pDCs can also promote the differentiation of CD24 + CD38hi B regulatory cells and plasmablasts via the expression of B cell maturation antigen (BCMA). Further, pDCs respond directly to apoptotic cells by secreting cytokines (IL-10, IL-6 and/or IFN-α) and inducing IL-10 secretion by T cells (Menon et al., 2016; Schuh et al., 2017; Simpson et al., 2016). Although, classically known for their IFN-α producing abilities, pDCs may act as antigen-presenting cells for both CD4+ and CD8+ T cells (Grouard, Rissoan, 1997, Rissoan et al., 1999). This functional variability is shown to be mediated by CpG oligonucleotide specificity (Kerkmann, Rothenfusser, 2003, Niessner et al., 2006, Sapoznikov et al., 2007, Villadangos and Young, 2008). CpG-B stimulated pDCs demonstrate upregulation of costimulatory and antigen-presenting molecules to function as APCs, whereas CpG-A activation promotes an IFN-α producing phenotype (Kerkmann, Rothenfusser, 2003). Gilliet and Liu also suggest that activation of pDCs by CD40L, rather than viral

3. Role of pDCs in immunity 3.1. Innate immune system pDCs are widely accepted as professional type I interferon producing cells. They express high levels of TLR9 and TLR7, which upon recognition of viral DNA or RNA, initiate MyD88-dependent phosphorylation of IRF-7 and induction of IFN-α gene transcription (Honda et al., 2005a; Honda et al., 2005b; Kadowaki et al., 2000; Kadowaki et al., 2001). Through the secretion of IFN-α and other pro-inflammatory cytokines, pDCs promote innate immune responses via the 4

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Fig. 3. pDC function in immunity. Through IFN-α secretion, pDCs serve to link the innate and adaptive immune systems via the induction of TH1 cell polarization, suppression of TH17 responses, promotion of CD8+ T cell survival and expansion and stimulation of antibody-producing plasma cell differentiation. Upon recognition of viral DNA or RNA, TLR9 activation initiates the MyD88-dependent phosphorylation of IRF-7 and IRF-5 transcription. Through IRF-5 activation of the NFκβ pathway and IRF7-mediated secretion of IFN-α, pDCs promote innate immune responses via the induction of NK cell migration and stimulation of macrophage and dendritic cells. Through expression of MHC and co-stimulatory molecules, pDCs promote adaptive immunity by acting as antigen-presenting cells for both CD4+ and CD8+ T cells. Additionally, pDCs also drive TH2 and Treg cell differentiation through the expression of IDO, inducible co-stimulator ligand (ICOS-L), OX40L and programmed death-ligand 1 (PD-L1).

viral infection (Diana, Brezar, 2011) and is seen in multiple myeloma (Ray et al., 2015), while upregulation of ICOS-L by pDCs has been implicated in immunosuppression in breast (Faget et al., 2013), ovarian (Conrad et al., 2012) and liver cancer(Pedroza-Gonzalez et al., 2015). Lastly, pDC upregulation of OX40L promotes melanoma progression through TH2 responses (Aspord et al., 2013), whereas increased Granzyme B production by pDCs has been shown to suppress T cell expansion (Jahrsdorfer et al., 2010) and is expressed by pDCs detected in head and neck squamous cell carcinoma (Thiel et al., 2011).

or CpG DNA, results in a tolerogenic pDC phenotype and subsequent development of regulatory T cells (Gilliet and Liu, 2002). Recent studies suggest that pDCs acting as APCs can induce tolerance either by carrying antigens to lymph nodes or via peripheral antigen capture and homing to the thymus where they induce the deletion of antigen-specific thymocytes (Hadeiba et al., 2012; Kohli et al., 2016). pDCs also induce a tolerogenic state through the expression of IDO (Boasso et al., 2007), inducible co-stimulator ligand (ICOS-L) (Ito et al., 2008), OX40L (Diana et al., 2009), programmed death-ligand 1 (PD-L1) (Diana et al., 2011) and Granzyme B (Jahrsdorfer et al., 2010). Increased pDC expression of IDO is shown to mediate tolerance in response to paracoccidioides brasilinesis (Araujo et al., 2016) and inhibit CD4+ T cell proliferation in HIV infection (Boasso, Herbeuval, 2007). Increased expression of PD-L1 by pDCs is demonstrated in response to

3.3. pDCs and Cancer The accumulation and dysfunction of pDCs has been implicated in contributing to the pathogenesis of a variety of cancers. Tumor cells are 5

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Fig. 4. pDC contribution to cancer pathogenesis. Tumor-induced pDC expression of ICOSL, PD-L1 and CLTA-4 promotes the establishment of an immunosuppressive microenvironment through the suppression of T cell responses and the activation of T regulatory cells. An impaired ability of TApDCs to produce IFN-α may be attributed to tumor-derived factors (e.g. TGF-β and TNF-α) or the downregulation of the IRF-7 pathway, which is required for IFN-α production. Loss of IFN-α production results in pDC-mediated tumor progression through the expansion of Treg cells and impaired NK cellmediated tumor elimination. pDC production of IDO, an enzyme that inhibits T cell proliferation, also contributes to tumor progression through immunosuppression.

Table 1 Role of pDCs in cancer pathogenesis. Type of Cancer

Role of pDC

Head and neck squamous cell carcinoma Ovarian Cancer

Promotion of tolerance via impaired pDC production of IFN-α and CD40-L induced Treg production (Gilliet and Liu, 2002, Hartmann et al., 2003) Promotion of tolerance via induction of IL-10 secreting CD8+ Treg cells and expansion of ICOS+Foxp3+ Treg cells (Conrad et al., 2012, Ito et al., 2007) Stimulation of tumor neovascularization via the production of TNF-α and IL-8 (Curiel et al., 2004, Zou et al., 2001) Promotion of tolerance via impaired pDC production of IFN-α (Sisirak et al., 2013a) ICOS-mediated expansion of Treg cells and increased IL-10 secretion (Faget et al., 2013) Promotion of tolerance via impaired IL-12 mediated TH1 response, decreased IFN- α secretion and increased Treg infiltration (Faith et al., 2007) Promotion of tolerance via OX40L and ICOSL-dependent differentiation of TH2 and Treg (Aspord et al., 2013, Ito et al., 2004) Tumor progression via induction of IL-5/IL-13 producing T cells and IL-10 producing Tregs (Aspord et al., 2013) Promotion of tolerance via impaired pDC production of IFN-α (Dey et al., 2015) Immunosuppression via IDO-mediated recruitment of regulatory T cells, PD-L1-mediated inhibition of T cell (Pallotta et al., 2011, Wainwright et al., 2012), Proliferation and increased tumor infiltrating ICOS+ Tregs (Faget et al., 2013, Gousias et al., 2013)

Breast Cancer Lung Cancer Melanoma Glioma

malignant ascites where they stimulate tumor neovascularization via the production of TNF-α and IL-8 (Curiel et al., 2004, Zou et al., 2001). Tumor-derived factors, such as TGF-β and TNF-α, drive TLR-activated TApDCs to favor maturation over IFN-α production (Labidi-Galy et al., 2011). TApDCs induce IL-10 secreting CD8+ Treg cells that promote a tolerogenic environment through the inhibition of tumor antigen-specific T cells (Wei et al., 2005). ICOS-L expressing TApDCs further contribute to the immunosuppressive tumor microenvironment by driving the activation and expansion of ICOS+Foxp3+ Treg cells (Conrad et al., 2012, Ito et al., 2007). This pDC-induced expansion of Treg cells via ICOS co-stimulation is also implicated in establishing an immunosuppressive microenvironment in liver and gastric cancers (Huang et al., 2014, Pedroza-Gonzalez et al., 2015). Breast cancer TApDCs demonstrate impaired IFN-α production upon TLR-mediated stimulation (Sisirak et al., 2013a). This impaired ability of TApDCs to produce IFN-α may be attributed to tumor-derived factors (e.g. TGF-β and TNF-α) or the downregulation of the IRF-7 pathway, which is required for IFN-α production and whose dysfunction is shown to promote breast cancer metastasis (Bidwell et al., 2012, Sisirak, Vey, 2013b). Loss of IFN-α production results in pDC-mediated tumor progression through the expansion of Treg cells and impaired NK cell-

shown to develop mechanisms that induce the tolerogenic function of pDCs to promote tumorigenesis (Fig. 4). Generally, tumors act to impair immunogenic pDC function through the expression of tumor derived immunosuppressive mediators and activation of pDC regulatory receptors (Demoulin et al., 2013). In this section, we will discuss the role of pDCs in specific cancers (Table 1). In patients with head and neck squamous cell carcinoma (HNSCC), Hartmann et al. demonstrate impaired IFN-α production by TApDCs in response to TLR9 stimulation by CpG oligonucleotides, possibly due to the downregulation of TLR9 (Hartmann et al., 2003). As previously discussed, pDCs that are inadequately activated by TLR agonists, are capable of promoting tolerance through CD40L induced Treg production (Gilliet and Liu, 2002, Hartmann, Wollenberg, 2003). In the tumor draining lymph nodes of patients with HNSCC, Hartmann et al. describes pDCs with a retained ability to produce IFN- α in response to CpG-induced activation, and drive CD4+ and CD8+ T cell activation (Gilliet and Liu, 2002, Hartmann, Wollenberg, 2003). These findings suggest that pDC dysfunction is related to tumor-induced suppression that does not appear to influence systemic pDCs in patients with HNSCC. In ovarian cancer, pDCs are recruited by SDF-1/CXCL12 to 6

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(Pashenkov et al., 2001). The role of pDCs in experimental autoimmune encephalomyelitis, an experimental model for MS, has been welldocumented and it has been shown that pDCs play a regulatory role in this model via the suppression of mDC-dependent induction of TH17 and TH1 cells as well as IDO-independent suppression of T cell cytokine production (Bailey-Bucktrout et al., 2008). Additionally, pDCs have been detected in postmortem brain tissue from stroke patients (Yilmaz et al., 2009) and are shown to be selectively recruited in CNS infections with West Nile Virus (Brehin et al., 2008, Yilmaz et al., 2009). In support of the findings that pDCs are recruited to the CNS in response pathological stimuli, our group previously found that pDCs were also the major APC present in glioma (Dey et al., 2015). Malignant gliomas (MG) are shown to secrete significant levels of CXCL12, CXCL9 and CXCL10, which were previously discussed as key chemokines responsible for pDC migration (Liu et al., 2011; Uemae et al., 2014). TApDCs in glioma patients demonstrate an impaired ability to produce IFN-α. This impaired pDC IFN-α production was also demonstrated in pDCs systemically and corresponds to a decrease in TLR9 expression (Dey, Chang, 2015). While the mechanism of pDC dysfunction in glioma is not fully understood, MGs are characterized by the presence of inhibitory cytokines (e.g. TGF-β), which have been shown to induce pDC dysfunction in other solid tumors (Bidwell et al., 2012, Sisirak et al., 2013b). In glioma, immunosuppression is established, in part, by TGF-β induction of IDO-mediated recruitment of regulatory T cells by pDCs (Pallotta et al., 2011, Wainwright et al., 2012). PD-L1 expression by TApDCs further aids in establishing immunosuppression by binding PD-1 expressing T cells, thereby inhibiting T cell proliferation and survival (Buchbinder and Desai, 2016). An increase in tumor infiltrating ICOS+ Tregs is also demonstrated in glioma and, as previously mentioned; ICOS-L expression by pDCs is thought to be responsible for the accumulation of ICOS+ TRegs in other cancers (Faget et al., 2013, Gousias et al., 2013). Further supporting an immunosuppressive role for pDCs in glioma, our group found that the depletion of pDCs during the early priming phase of tumor progression resulted in a decrease in Tregs and ICOS+ Treg cells within the murine tumor environment (Dey et al., 2015).

mediated tumor elimination (Rautela et al., 2015; Sisirak et al., 2012). As in ovarian cancer, the ICOS-mediated interaction between TApDCs and CD4+ T cells is thought to be a mechanism underlying the expansion of Treg cells and increased IL-10 secretion in breast cancer (Faget et al., 2013). In patients with lung cancer, pDCs are found to infiltrate draining lymph nodes and, unlike the TApDCs mentioned previously, these pDCs express detectable levels of TLR9 and, upon exposure to TLR-agonists, retain the ability to produce IFN-α and promote T cell responses (Faith et al., 2007). These lymph node pDCs do, however, demonstrate impaired IL-12 secretion, which is important for the induction of the TH1 response (Faith et al., 2007). pDCs are also shown to infiltrate tumors and be increased in the bone marrow of patients with non-small cell lung carcinoma (Perrot et al., 2007; Shi et al., 2014). According to Perrot et al., these pDCs express an immature phenotype (lack CD83), lack expression of important activation markers (e.g CD80/86) and on TLR-mediated activation induce only weak IFN-α secretion and T cell proliferation (Perrot et al., 2007). This increase in TApDCs associated with enhanced immunosuppression, increased Treg infiltration, and decreased mDCs (Sorrentino et al., 2010). In melanoma patients, pDC infiltration of lymph nodes and cutaneous lesions is associated with early relapse (Aspord et al., 2014). Unlike previously discussed cancers, TApDCs in melanoma demonstrate increased expression of co-stimulatory molecules and produce IFN-α on TLR-mediated activation. These TApDCs, which are induced by CCL17, CCL22 and MMP2 to increase expression of OX40L and ICOSL, drive the differentiation of CD4+ T cells into TH2 and Tregs. These T cells subsequently establish an immunosuppressive environment that promotes tumor progression through the secretion of various cytokines including, IL-5, IL-13 and IL-10 (Aspord et al., 2013, 2014). The increased expression of immune mediators, CTLA-4, OX40, and PD-1, has also been demonstrated in several cancers (Aspord et al., 2013, Montler et al., 2016, Schutz et al., 2017). pDCs are shown to express ligands for these receptors and their interaction with OX40, PD1 or CTLA-4 bearing cells leads to the suppression of antitumor immunity (Aspord et al., 2013, Schutz et al., 2017). In patients with chronic myeloid leukemia, increased expression of CD86, a CTLA-4 ligand, by pDCs is correlated with increased risk of relapse (Schutz et al., 2017). As previously discussed, in melanoma pDC expression of OX40 and ICOS ligands promotes tumor progression through the induction of IL-5/IL-13 producing T cells and IL-10 producing Tregs (Aspord et al., 2013). Ito et al. has also shown that OX40L expressing pDCs produce little IFN-α and induce TH2 responses through interactions with OX40 bearing cells (Ito et al., 2004). The high level of PD-L1 expression on the surface of pDCs and tumor cells may also contribute to the progression of cancer. Through interactions with PD-1 expressing T cells, PD-L1 bearing pDCs can inhibit T cell responses (Patsoukis et al., 2012, Ray et al., 2015). Recently, Patsouksi et al. suggested that this PD-1-mediated inhibition of T cell differentiation may be due to PD-1 induced metabolic reprograming, which inhibits T cell glycolysis in favor of fatty acid oxidation (Patsoukis et al., 2015). These findings, which suggest an inhibitory role for PD-L1+ pDCs, contrast a recent study demonstrating a PD-L1+ pDC subset specialized in type I IFN production and found to be elevated in the blood and skin of patients with type I IFN-mediated autoimmune diseases (Alculumbre et al., 2018).

4. Clinical significance 4.1. Induction of pDC IFN-I production Type I interferons are known to play a key role in antitumor immunity through their influence on a wide variety of immune cells (Snell et al., 2017). The finding that impaired IFN-α production has been noted in many types of cancers, generated excitement at the prospect of utilizing IFN-α therapy to combat these malignancies (Hartmann et al., 2003). However, this enthusiasm was blunted by the realization that IFN-α administration not only displayed low efficacy, but also was also associated with potentially serious adverse side effects and systemic toxicity (Weber et al., 2015). However, IFN-α administration has demonstrated some promising results, most notably in the treatment of hematologic malignancies (Zitvogel et al., 2015). Additionally, IFN-α is shown to be required for the success of conventional chemotherapy, radiotherapy, immunotherapy and targeted anticancer agents (Zitvogel et al., 2015). These findings indicate that the successful clinical application of IFN-α therapy may require capitalizing on endogenous mechanisms of IFN-α production and suggest a possible role for the exploitation of pDCs. pDCs, which are known to produce type I interferon, exhibit a high degree of tumor infiltration. Why, then, is the accumulation of pDCs within the tumor environment shown to correlate with negative outcomes in cancer (Sisirak et al., 2012)? In contrast to their normal role in the production of high levels of IFN-α, TApDCs demonstrate impaired IFN-α secretion, increased expression of immunosuppressive mediators (i.e. IDO, PD-L1, OX40L), and the ability to suppress T cell responses and promote Treg expansion. Therefore, inducing an IFN-α producing

3.4. pDCs in CNS and glioma While pDCs are not frequently found in healthy brain parenchyma, they have been detected in the CSF of healthy patients and are shown to accumulate in the CNS in response to inflammatory stimuli (Hart and Fabre, 1981; Pashenkov et al., 2001). pDCs were also found to be minimally present in patients suffering from non-inflammatory neurological diseases, but exhibit the highest numbers in the CSF of patients suffering from neuroinflammatory conditions such as multiple sclerosis (MS), optic neuritis, neuroborreliosis and aseptic meningoencephalitis 7

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response and increased length of survival has not been achieved in the majority of patients (Filley and Dey, 2017). Our group recently demonstrated that the subtype of dendritic cell (mDC or pDC) selected for vaccine development impacts the efficacy of such therapies in a murine model of glioma. We showed that the use of an mDC-based vaccine resulted in a superior anti-glioma T cell response and prolonged survival when compared to the pDC-based therapy (Dey, Chang, 2015). On the other hand, Tel et al. demonstrated that the administration of activated pDCs into the lymph nodes of patients with metastatic melanoma resulted in increased systemic IFN-α production and the induction of antigen-specific T- and B-cell responses (Tel et al., 2013). Additionally, they found that 1- and 2-year survival rates were increased after pDC vaccination to 60%, and 45%, compared to 30% and < 10% in controls. The results of other preclinical and human clinical trials also suggest a promising role for the use of DC-based vaccine therapy in cancer (Filley and Dey, 2017). However, the efficacy of DC-based vaccine therapy appears to be dependent on the ability to simultaneously induce a vigorous anti-tumor immune response and eradicate tumor-induced immune suppression mechanisms.

phenotype in TApDCs, which would simultaneously eliminate their suppressive activities, could serve as a mechanism for establishing targeted IFN-α therapy. Candolfi et al., explored this exploitation of pDCs to induce antitumor immunity by demonstrating that adenovirusmediated delivery of Flt3L and thymidine kinase (TK) resulted in tumor regression and increased length of survival via the expansion and recruitment of pDCs in a murine glioma model (Candolfi et al., 2012). These tumor-infiltrating pDCs were able to secrete IFN-α, prime T cells and, unlike Ad-IFN-α, Ad.T/GCV + Ad.Flt3L administration was not associated with adverse neurological or systemic effects (Candolfi et al., 2012). Studies are also currently investigating the use of CpG oligodeoxynucleotide (ODNs) multimers to induce pDC IFN-α production and promote potent anticancer immune responses (Gungor et al., 2014). CpG ODN-activated pDCs also demonstrate an up-regulation of CCR7, a receptor implicated in homing pDCs to T cell rich regions of lymphoid tissue and an enhance ability to induce NK and CD8+ T-cell eradication of established tumors (Kawarada et al., 2001; Krug et al., 2001). The use of TLR agonists is complicated, however, by the finding that pDC dysfunction in tumor microenvironments is likely related to the downregulation CpG ODN-targeted TLRs (Dey et al., 2015).

5. Future directions and challenges 4.2. Immune checkpoint blockade Future directions need to be focused on understanding the precise molecular mechanisms how the tumor cells cross talk/influence the pDC specific functions in vivo with special emphasis on tumor heterogeneity and host genetic architecture. Identification of specific pathways which were influenced by tumors cells will lead to development of therapeutic modalities to revert these tumor induced alteration and enhance the antitumor immune functions of pDC. The major challenges in this approach are developing the pre-clinical model system with the representative tumor heterogeneity.

Another method for targeting pDC dysfunction is through the use of immune checkpoint inhibitors, which have shown success in the treatment of a variety of cancers (Wolchok, 2015). In support of a PD-1 blockade to overcome pDC dysfunction, Ray et al. demonstrated that inhibition of the PDL1-PD1 interaction in multiple myeloma patients resulted in an increase in CD4+ and CD8+ T cells, enhanced response of pDC-activated CD8+ CTLs and NK cells, and impaired pDC-mediated immune suppression (Ray et al., 2015). ICOS-L, whose expression is also used by pDCs to establish tolerance, is demonstrated to be another potential target for pDC-directed therapy (Zheng et al., 2013). Zheng et al., have shown that an ICOSICOSL blockade results in decreased generation and suppressive abilities of CD4+ Treg cells, and corresponds to decreased CD4, Foxp3 and CTLA-4 expression (Zheng et al., 2013). Other individual checkpoint inhibitors have also produced promising results; recently, attention has been more focused on the use of combination blockades. Wainwright et al., found that the use of a combined CTLA-4, PD-L1, IDO blockade resulted in decreased Treg levels in murine glioma models and Montler et al., have provided rationale for the use of a combined anti-OX40, anti-PD-1, and anti-CTLA-4 blockade in the treatment of HNSCC (Montler et al., 2016, Wainwright et al., 2014). Currently, there are several ongoing clinical trials investigating the safety and efficacy of these combination checkpoint blockades in glioblastoma patients (Huang et al., 2017).

6. Conclusion As major regulators of critical immune responses, pDCs present an interesting challenge for investigators and clinicians alike. pDCs are necessary for the initiation of immune responses against pathogens, but are also critical in maintaining the equilibrium between immunity and tolerance. Given their important regulatory role, it should come as no surprise that pDC dysfunction contributes to the pathogenesis of many diseases, including cancer. In cancer, pDC dysfunction is demonstrated by decreased IFN-α production and increased suppression of anti-tumor immunity. As type I IFNs are necessary for both exogenous and endogenous tumor destruction, the challenge rests in eliminating pDCinduced immune suppression and promoting IFN-α-induced anti-tumor responses without causing a state of devastating autoimmunity. Understanding precisely how pDCs develop and what factors regulate their function will be key in developing future pDC-targeted therapies that do not greatly disrupt the balance of immunity and tolerance.

4.3. pDC depletion In lieu of inducing or inhibiting selective functions of TApDCs, some studies have suggested promoting antitumor immunity by eradicating pDCs from the TME altogether. Gil et al. demonstrated that the use of a virally expressed CXCR4 antagonist results in the inhibition of TApDC accumulation, reduced metastasis and improved overall survival in ovarian cancer (Gil et al., 2014). Our group also found that depleting pDCs during the early phase of tumor progression resulted in a decrease in Tregs and ICOS + Tregs, and provided a survival advantage in a murine model of glioma (Dey et al., 2015).

Competing interests

4.4. Dendritic cell vaccine

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The use of dendritic cell-based vaccines to induce anti-tumor T cell responses has shown promising results in animal models and several human malignancies. While DC-based vaccine therapies have proven capable of inducing robust, tumor-specific T cell responses, clinical

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“The authors declare that they have no competing interests.” Acknowledgements This work was supported by the NIHK08NS092895 grant (MD). Authors would like to thank Christopher Brown for his help with the figure illustrations.

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