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