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

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.

Keywords: Antigen presentation; Cytokine; Dendritic cell; Molecular regulation; STAT; Tumor.

Fig. 1. Identification and localization of mouse and human DC subsets

The major DC populations in lymphoid and non-lymphoid organs of mouse and human are indicated by cross species markers recently identified by (Guilliams et al., 2016). Tissue-specific DC markers are highlighted in red.

Fig. 2. Schematic illustration of trafficking and activation or tolerance signals regulating CD103⁺ cDC1s in the TME

Pre-cDCs migrate to the TME, differentiate into CD103⁺ cDC1s, and integrate a variety of activating or tolerogenic signals, as shown. Tumor-associated CD103⁺ cDC1s subsequently migrate to the TdLNs to prime anti-tumor naïve CD8⁺ T cells. CD103⁺ cDC1s in the TME also secrete chemokines that recruit anti-tumor T cells, as indicated.

Fig. 3. DC vaccine-based clinical trials

The graph shows the number of DC vaccine-based clinical trials in distinct cancers listed on clinicaltrial.gov from November 1999 to March 2017. Information for the following cancers is included: central nervous system (CNS) tumors (Medulloblastoma, Ependymoma, Gliobastoma Multiforme and Astrocytoma); genitourinary (GU) tumors (Prostate); skin tumors (Melanoma); gastrointestinal (GI) tumors (Colorectal, Pancreas, Esophagus); lung tumors (Mesothelioma, Adenocarcinoma, Non-Small Cell lung cancer, Small cell lung cancer); renal tumors (Renal cell carcinoma); breast tumors (Ductal carcinoma in situ); other solid tumors (Sarcomas, Neuroblastoma, Wilm’s Tumor, Ewing’s Sarcoma and Rhabdomyosarcoma); and hematological malignancies (Acute Myeloid Leukemia, Myeloma, Lymphoma).