Elsevier

Molecular Immunology

Volume 110, June 2019, Pages 24-39
Molecular Immunology

Molecular regulation of dendritic cell development and function in homeostasis, inflammation, and cancer

https://doi.org/10.1016/j.molimm.2018.01.014Get rights and content

Highlights

  • Dendritic cells (DCs) comprise the primary antigen presenting cells in the immune system.

  • DCs are key mediators of immune tolerance and immune responses against tumors.

  • Cytokines and cytokine-responsive STAT transcription factors have principal roles in regulating DC differentiation and function.

  • Type 1 conventional DCs (cDC1s) are specialized in delivering tumor-associated antigens to lymph nodes to activate cytotoxic T cells.

Abstract

Dendritic cells (DCs) are the principal antigen-presenting cells of the immune system and play key roles in controlling immune tolerance and activation. As such, DCs are chief mediators of tumor immunity. DCs can regulate tolerogenic immune responses that facilitate unchecked tumor growth. Importantly, however, DCs also mediate immune-stimulatory activity that restrains tumor progression. For instance, emerging evidence indicates the cDC1 subset has important functions in delivering tumor antigens to lymph nodes and inducing antigen-specific lymphocyte responses to tumors. Moreover, DCs control specific therapeutic responses in cancer including those resulting from immune checkpoint blockade. DC generation and function is influenced profoundly by cytokines, as well as their intracellular signaling proteins including STAT transcription factors. Regardless, our understanding of DC regulation in the cytokine-rich tumor microenvironment is still developing and must be better defined to advance cancer treatment. Here, we review literature focused on the molecular control of DCs, with a particular emphasis on cytokine- and STAT-mediated DC regulation. In addition, we highlight recent studies that delineate the importance of DCs in anti-tumor immunity and immune therapy, with the overall goal of improving knowledge of tumor-associated factors and intrinsic DC signaling cascades that influence DC function in cancer.

Introduction

Similar to other immune lineages, fully differentiated DCs comprise distinct subsets that differ in function, morphology, and anatomical location. DC subsets arise from specified hematopoietic progenitors, and require unique transcriptional and signaling programs for their development and functional responses. In some cases, DC transcriptional and signaling responses are activated or repressed by extracellular factors in the tumor microenvironment (TME), such as cytokines, which influence DC function. Furthermore, recent work indicates the importance of specific DC populations such as cDC1s in tumor immunity and immune therapy. Nonetheless, the potential for DC use in cancer treatment remains largely untapped. Improved understanding of DC regulation during development and in the TME is necessary for generating novel cancer therapies and effectively reducing the burden of this devastating disease. Towards this aim, we review molecular mechanisms controlling DCs, with a specific focus on cytokines and cytokine-activated STATs, as well as roles for specific DC subsets in cancer and cancer therapy.

Section snippets

DC subsets and cross species identification

In steady state conditions, DCs are customarily divided into two major populations, the conventional or classical DC (cDC) subsets and the plasmacytoid DCs (pDCs) (Fig. 1). Traditionally, the cDCs are recognized as the professional antigen-presenting cells, while pDCs are major producers of type I interferons (IFN-Is). Moreover, the cDC subsets comprise type 1 cDCs (cDC1s) and type 2 cDCs (cDC2s), which also differ in function, localization, and morphology. Canonical surface marker (phenotypic)

DC activation and antigen presentation

DCs are the principal immune population bridging the innate and adaptive immune systems. This is due to their ability to recognize a variety of microbial-, pathogen-, and danger-associated molecular patterns (i.e., MAMPs, PAMPs, and DAMPs) via an “innate” response, and subsequently undergo maturation or activation events that promote their antigen-presenting functions and enable their regulation of antigen-specific adaptive immune responses. DC activation by MAMPs, PAMPs, and DAMPs is mediated

DC growth factors and the TME

Several DC growth factors have important roles in mediating immune responses to tumors, although it is important to point out that certain growth factors also stimulate additional immune subsets as discussed below. Pioneering work in this area was done using B16 melanoma cells transduced with virus encoding GM-CSF, which caused GM-CSF secretion from the engineered tumor cells. Since GM-CSF was originally identified as a principal DC growth factor, this approach was used to increase DC migration

Accurate DC identification in tumors

Early studies indicated that tumor-infiltrating DCs are defective in their ability to stimulate T cells and drive anti-tumor immune responses, thus enabling tumor growth. This was attributed to reduced expression of co-stimulatory molecules and subdued production of pro-inflammatory cytokines, along with elevated expression of inhibitory molecules such as PD-L1, by tumor associated DCs (Perrot et al., 2007; Stoitzner et al., 2008). These studies utilized CD11c and MHC II expression to identify

DC-based therapies and tumor vaccines

Various regimens, including those that mimic DC-expressed activating ligands for T cells (e.g., 4-1BB, OX40 agonist, CD40L), agents that stimulate DCs directly (e.g., CD40 agonists, TLR agonists), or mechanisms that block DC-mediated negative signals (e.g. anti-CTLA, anti-PD-1, anti-PD-L1) have been studied extensively in experimental tumor models and, in many cases, tested in clinical trials for cancer (Eriksson et al., 2017; Freeman et al., 2000; Latchman et al., 2001; Leach et al., 1996;

Concluding remarks

Studies over the last few decades have revealed important transcriptional and cytokine-driven pathways regulating DC differentiation. Moreover, DC function is dynamically modulated by microenvironmental factors including cytokines and chemokines present in the TME. In many cases, these elicit immunosuppressive activities and understanding mechanisms by which these inhibitory pathways can be circumvented is key to improving DC based immunotherapy. In exciting advances, several current studies

Declaration of interest

The authors declare no competing financial interests. None of the authors affiliated with this manuscript have any commercial or associations that might pose a conflict interest.

Acknowledgement

This study was supported by grants from the NIH National Institute of Allergy and Infectious Diseases (R01AI109294 to S.S.W.), a Research Training Award from the Cancer Prevention and Research Institute of Texas (CPRIT RP170067 to T.T.C), and the MD Anderson Center for Inflammation and Cancer (to S.S.W. and H.S.L.)

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