Elsevier

Journal of Neuroimmunology

Volume 322, 15 September 2018, Pages 63-73
Journal of Neuroimmunology

Review Article
Plasmacytoid dendritic cell in immunity and cancer

https://doi.org/10.1016/j.jneuroim.2018.06.012Get rights and content

Highlights

  • pDCs represent a small fraction of circulating DCs and play a dynamic role in bridging innate and adaptive immunity.

  • Besides producing large amount of IFN-alpha in the setting of viral infection pDCs can also act as professional APCs.

  • pDCs have been shown to play regulatory role in several cancers and help tumor progression.

  • Understanding the tumor influence on pDC function in TME can lead to the development of novel anti-cancer immunotherapies.

Abstract

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 pDC-targeted therapy.

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, 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 P1-pDC 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 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.

Section snippets

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

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 induction of NK cell migration and

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

Future directions and challenges

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

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

Competing interests

“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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