Pathogen-Related Signal Transduction Pathways of Dendritic Cells: Perspectives for Cancer Immunotherapy

Tomonori      Kato; Yasuji      Ueda; Hiroaki      Kinoh; Kaori      Tsukada; Tomohiko      Ichikawa; Yoshikazu      Yonemitsu

Abstract

Dendritic cells (DCs) play a crucial role in translating innate to adaptive immunity. DC-based cancer immunotherapy has been under evaluation; however, its clinical benefits remain limited. A better understanding of DCs is, therefore, needed to improve clinical outcomes. Toll-like receptors (TLRs) were initially identified as molecules that recognize and bind pathogen-associated molecular patterns (PAMPs) leading to DC maturation. The TLR signaling pathway leads to the activation of NF-κB, which initiates the transcription of proinflammatory cytokine genes. As the sensors of RNA viruses in the cellular cytoplasm, RNA helicases containing retinoic acidinducible gene-I (RIG-I) have been shown to recognize the viral RNA genome, and recent studies have demonstrated that these helicases strongly induce the upregulation of type I interferons. We recently demonstrated that RNA viruses strongly activated DCs, and this finding is expected to aid in the development of improved DC-based cancer immunotherapy. We then proposed DC-based “immunostimulatory RNA virotherapy” as a novel therapeutic approach. The janus kinases (JAKs) and the signal transducers and activators of transcription (STATs) are key molecules in a major signaling pathway for modulating DC function; suppressors of cytokine signaling (SOCSs) inhibit this pathway. Some recent studies have suggested that the suppression of SOCS family proteins in DCs modulates immune responses, including anticancer immunity. Here, we review recent progress in the elucidation of the mechanisms of signal transduction pathways in DCs; it is hoped that such investigations will eventually lead to a variety of DC-based cancer immunotherapies.

Keywords: RNA virus, dendritic cell, cancer immunotherapy, TLRs, RIG-I, SOCS