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Review
. 2013 Feb;34(2):67-73.
doi: 10.1016/j.it.2012.10.004. Epub 2012 Oct 31.

Type I interferon response and innate immune sensing of cancer

Mercedes B Fuertes  1 , Seng-Ryong Woo, Byron Burnett, Yang-Xin Fu, Thomas F Gajewski
Affiliations
Review

Type I interferon response and innate immune sensing of cancer

VSports app下载 - Mercedes B Fuertes et al. Trends Immunol. 2013 Feb.

Abstract

Unexpectedly, many cancers appear to induce a spontaneous adaptive T cell response. The presence of a T cell infiltrate has been linked to favorable clinical outcome in multiple cancer types. However, the innate immune pathways that bridge to an adaptive immune response under sterile conditions are poorly understood. Recent data have indicated that tumors can induce type I interferon (IFN) production by host antigen-presenting cells (APCs), which is required for a spontaneous T cell response in vivo. The innate immune sensing pathways that trigger type I IFN production are being elucidated VSports手机版. Host type I IFNs are also required for optimal therapeutic efficacy with radiation. This recently uncovered role for host type I IFNs for antitumor immunity has important fundamental and clinical implications. .

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Figures

Figure 1
Figure 1. Major intracellular pathways leading to type I IFN production
Cytosolic dsDNA can be directly recognized by the receptors DAI and IFI16 (and its mouse ortholog p204) which induces a STING-dependent activation of TBK-1 and Ikkε that triggers IRF-3/7 phosphorylation, dimerization, nuclear translocation, and type I IFN gene transcription. The dsDNA can be also recognized by RNA pol III that transcribes it to RNA, activating helicase RIG-1 (and MDA5) that signals through IPS-1 and also activates TBK-1, resulting in type I IFN production. In the endosomal compartment TLR-3 and TLR-4 can also activate TBK-1 and Ikkε to induce IRF-3/7 phosphorylation leading to type I IFN production, but through TRIF and TRAF3. Also in endosomes, TLR-9 and TLR-7/8 associate with MyD88 upon recognition of nucleotide ligands, leading to a signaling cascade that involves IRAK-4, TRAF6 and IRAK-1 that triggers IRF-7 activation and induction of type I IFN production. Most of these pathways have been defined using infection models, and their potential role in tumor sensing is being elucidated.
Figure 2
Figure 2. Working model for how host type I IFNs contribute to a spontaneous adaptive T cell response against tumors in vivo
Tumor-derived factors seem to induce the early production of IFN-β by host CD11c+ DCs. Subsequently, this IFN-β acting on the CD8α+ DC subset stimulates the cross-presentation of tumor derived antigens leading to the cross-priming of tumor antigen-specific CD8+ T cells. These activated T cells may, in turn, traffic to tumor sites and induce further tumor cell death.
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