**4. Plasmacytoid dendritic cells (pDC)**

The pDCs constitute ~0.01–0.04% of PBMCs and commonly reside in secondary lymphoid organs localising in the follicular cortex, T cell nodules and around high endothelial venules [36, 37]. As their name suggests, pDCs are similar in morphology to that of plasma cells. Under light microscopy, pDCs are observed to be spherical in shape with a rounded nucleus, often predominant endoplasmic reticulum and present as clusters in T-cell rich regions of lymphoid tissue [36–38].

The pDCs, originally identified as 'natural interferon producing cells' (NIPC), are renowned for their ability to drive immense type I and type III IFN production via TLRs 7 and 9 [39–41]. This IFN production is essential to combat viral infection but pDC-derived IFN is also thought to contribute to disease in autoimmune diseases including systemic lupus erythematosus [42]. They are also thought to play a role in Th2 induction and asthma progression in humans [42]. Conversely, pDC have also been shown to play a major role in tolerance *in vivo*, through their production of IDO and TGF-beta [42].

pDCs are recognised as being CD11c<sup>−</sup>/loCD45RA+ CD123+ CD303+ CD304+ HLA-DR+ and can express CD56 (reviewed in [2]). pDCs may also be identified by their transcription factors including; TCF4 (also known as E2-2), SPIB, ZEB2, IRF8, IRF7 and IRF4 [43–45]. Haploinsufficiency in the *TCF4* gene results in Pitts-Hopkins syndrome, which characteristically generates defective pDCs, illustrating a dependence of this factor for normal human pDC development [46].

The pDCs can be divided into 2 subsets based on CD2 expression [47]. Recent single cell transcriptomic profiling of blood DCs from healthy donors has revealed that CD2<sup>+</sup> 'pDC' also express AXL and SIGLEC6 (known as AS DCs). These AS DCs can stimulate CD4<sup>+</sup> and CD8<sup>+</sup> allogeneic T cell proliferation whereas the segregation of pDCs away from contaminating AS DCs demonstrated potent IFN-α production after TLR9 stimulation and a lack of T cell priming attributes [8]. Whether AS DCs and pDC are 2 distinct cell types or differentiation stages of one another is yet to be defined.

**105**

*Dendritic Cells and Their Roles in Anti-Tumour Immunity*

A rare and highly aggressive acute leukaemia known as Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) involves the malignancy of pDC precursors [48], driven, at least in part by the juxtaposition of the pDC-specific RUNX2 enhancer and the MYC promotor due to the chromosomal translocation (6;8) (p21;q24) [49]. The BPDCN can be reliably identified by immunohistochemical staining with TCF4 and CD123 antibodies [50]. BPDCNs most commonly present as skin lesions and may be accompanied by swelling of other organs such as the lymph nodes, bone marrow or spleen. Standard chemotherapy treatments for myeloid neoplasms often result in poor prognosis [51] although a toxin-conjugated anti-CD123 drug, tagraxofusp-erzs, has recently been approved as the first FDA-approved

Monocyte derived DC (moDC) refers to DCs induced from monocytes with GM-CSF *in vitro.* These tissue culture systems originated in the early 1990s based on work showing varying combination of cytokines with GM-CSF could induce the acquisition of antigen presentation capacity in stem cells and CD34<sup>+</sup> blood precursors [53–56], and this was optimised with the addition of IL-4 [57]. These systems have been an immensely popular tool for more than two decades for *in vitro* research pertaining to conventional DC biology and immunological function. They have been particularly useful in human research due to the difficulties in obtaining large numbers of *ex vivo* primary human DC for research. However, the feasibility of these models has recently been questioned, detailed analyses of GM-CSF induced DC cultures reveal a heterogeneous population of macrophages and conventional DCs, with the MHCIIhi cells the most

It still remains unclear whether the moDC actually represent an *in viv*o equivalent cell subset. They potentially represent an *in vitro* equivalent of an inflammatory monocyte known as TNF/iNOS producing DCs (TipDCs), based on their surface phenotype [62], cytokine profile and a shared precursor [62]. Importantly, high intra-tumoral expression of CD40L, TNF-α and iNOS, key phenotypes of TipDCs, were strongly correlated with substantially higher long term disease free survival rates over 10 years in patients with colorectal cancer [63]. Therefore, moDCs may

While the *ex vivo* induced moDC do not recapitulate *bona fide* DC subsets, the ease of isolation and culture has made the moDC a popular vaccine candidate in human clinical trials since the late 1990s. However, results from clinical trials using moDC in cancer immunotherapies for various cancer types have been modest at best [64*,* 65]. In a more recent phase II trial of patients with surgically resectable liver metastatic colon adenocarcinoma, vaccination of patients with autologous tumour lysate pulsed moDC conferred interim protection, demonstrating a 3-fold increase in the median disease free survival compared to the control arm of the study [66]. The continued refinement of moDC preparations and the choice of

The ability to present Ag and activate the adaptive immune response makes DCs an attractive target to re-invigorate anti-cancer immunity. There are different types of DC vaccines, with the most common type involving the *ex vivo* maturation

represent a useful and relevant *in vitro* model of inflammatory DCs.

antigens, may see future improvements of DC cancer vaccines.

*DOI: http://dx.doi.org/10.5772/intechopen.91692*

BPDCN-specific treatment [52].

**5. Monocyte derived DCs**

DC-like [58*–*61].

**5.1 MoDC and cancer vaccines**

*Dendritic Cells and Their Roles in Anti-Tumour Immunity DOI: http://dx.doi.org/10.5772/intechopen.91692*

A rare and highly aggressive acute leukaemia known as Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) involves the malignancy of pDC precursors [48], driven, at least in part by the juxtaposition of the pDC-specific RUNX2 enhancer and the MYC promotor due to the chromosomal translocation (6;8) (p21;q24) [49]. The BPDCN can be reliably identified by immunohistochemical staining with TCF4 and CD123 antibodies [50]. BPDCNs most commonly present as skin lesions and may be accompanied by swelling of other organs such as the lymph nodes, bone marrow or spleen. Standard chemotherapy treatments for myeloid neoplasms often result in poor prognosis [51] although a toxin-conjugated anti-CD123 drug, tagraxofusp-erzs, has recently been approved as the first FDA-approved BPDCN-specific treatment [52].
