The extrinsic RNA-sensing pathway for adjuvant immunotherapy of cancer

Abstract

Infection with RNA viruses presents a typical pattern of virus products, double-stranded RNA (dsRNA), and induces the maturation of antigen-presenting dendritic cell (mDC). There are several dsRNA sensors that are differentially distributed on the cell membrane and in the cytoplasm and are variably expressed depending on the cell type. Among these sensors, TLR3 links to the adaptor TICAM-1 (TRIF), which is characterized by its unique multipronged signaling cascades for cytokine/chemokine production, apoptosis and autophagy in both immune and tumor cells. In the context of mDC maturation, various cellular events are further induced in response to dsRNA; these include cross-priming followed by CD8+ CTL induction, NK activation and proliferation of CD4+ T cells including Th1, Th2, Treg and Th17 cells. In this review, we focus on the potential role of dsRNA in modulating the inflammatory milieu around mDCs and tumor-associated antigens to drive specific cellular effectors against the tumor.

Fig. 1

dsRNA-sensing systems. a Double-stranded (ds)RNA are primarily generated during virus replication. Major dsRNA sensors in human cells are indicated. Dicer and RNA-recognizing helicases work in invertebrates as antiviral receptors, but in humans no evidence of these receptors for antiviral action has been proposed. How dsRNA selects a variety of RNA pattern sensors remains largely unknown. PTGS, post-transcriptional gene silencing. b TLR3 is mainly localized in the endosome of limited cell types, while RLH (RIG-I and MDA5) are ubiquitously distributed in the cytoplasm. Adaptor molecules, TICAM-1 and MAVS, are localized in the cytoplasm. Upon stimulation, TLR3 recruits TICAM-1 near the endosomal membrane, while MAVS recruits RLH on the mitochondrial membrane. The known outputs of TLR3 and RLH are indicated by red

Fig. 2

An outline of the TICAM-1 pathway. a In human cells, TICAM-1 once detached from TLR3 serves as a signaling platform to induce apoptosis, autophagy, NK activation and cross-priming. TICAM-1 undergoes some modification secondary to complex formation with TLR3, forms multimer, and dissociated from TLR3 with unknown mechanism. The pathways for NK activation, CTL induction and autophagy are only partially identified, although the pathway for apoptosis is getting clarified. Although epithelial cells in bronchi, bile-duct and intestine express TLR3 on their surface membranes, it is undetermined whether surface-expressed TLR3 retains the cellular responses. b The N-terminal ‘Effector-driving site (EDS)’ recruits appropriate signal-transmitting molecules and matures mDCs leading to induction of effector cells, including NK and CTL. The C-terminal RHIM domain participates in signal transmission for apoptosis and autophagy. TICAM-1-binding proteins, either direct or indirect, are summarized in the inset table

Fig. 3

Various effectors driven by the TICAM-1 pathway in mDCs. The effectors can be induced through the TICAM-1 pathway in mDCs are delineated in this figure. In an early phase of infection, cytokines and IFNs are released in response to microbial patterns. Later, the cellular effectors are induced secondary to activation of the TICAM-1 pathway in mDCs

Fig. 4

Possible NK-inducing pathways against cancer. NK activation is an example of mDC output. For full activation, NK cells have to be supported by dendritic cells (myeloid DCs in this figure) that recognize pathogen-associated molecular patterns (PAMPs). In general, NK cells and dendritic cells are reciprocally activated by soluble signals and cell/cell contact. Since the tropism of the pathogen varies, the main NK activating players are determined by which sensor cells are attacked by the pathogens and induce innate signals for NK activation