Abstract 5396: Interferon-α receptor dependent and independent inhibition of type I interferon production in plasmacytoid dendritic cells from mice and melanoma patients
Authors: Xue-Fei Huang, Alexander Gelbard, Haiyan S. Li, Tania G. Rodríguez-Cruz, Yanyan Lou, Chengwen Liu, Yared Hailemichael, Vashisht G Yennu Nanda, Michael A. Davies, Yong-Jun Liu, Stephanie S. Watowich, Willem W. Overwijk
Journal: Cancer Research (2012)

Abstract IFN-α is pleiotropic cytokine belonging to the type I Interferon (IFNs) family and can induce multiple biological effects, e.g. induction of apoptosis and inhibition of cell growth. These cytokines exhibit a long record of clinical use in patients with some types of cancer and viral diseases. Notably, certain autoimmune disorders have been postulated to be mediated by endogenous IFN-α and are often observed in some IFN-α-treated cancer patients. How IFN-α promotes the generation of antitumor T-cell immunity and its regulation mechanisms are still unclear. To address these questions, we focus on the main producer of IFNs, Plasmacytoid dendritic cells (pDCs), which reside in bone marrow and lymphoid organs and typically secrete type I IFNs on Toll-like receptor (TLR) triggering. We detected cytokines production by human pDCs from leukapheresis cells of melanoma patients who were treated with IFNs for 25 weeks. After stimulation with CpG-A, these pDCs after treatment (IFN-α-pDCs) produce 70% less IFN-α compare to before treatment, but compatible amount of other inflammatory cytokines e.g. IL-6. We observed the similar phenomena in murine models either after VSV infection or by systemic IFN-α delivery. We showed that these IFN-α-pDCs possess more active and mature morphology as DCs and they are particularly more effective in inducing T- and NK-cell immunity by increasing cell proliferation and differentiation. Of note, IFN-α-pDCs skewed the naïve CD4+ T cells to a Th17 antigen-presenting subset by producing more IL-17 but less IFN-γ compare to wide type pDCs. The ensemble of these results suggests that IFN-α-pDCs could be successfully used in strategies of cancer immunotherapy, especially in melanoma patients. We also demonstrate that pDCs possess two fundamental, but separate, physiologic mechanisms for negative feedback control of IFN-α production after IFNs treatment in melanoma patients. Both signaling through the canonical TLR-MyD88 pathway and feedback inhibition from IFN-α itself through the IFN-α/βR render pDCs unable to synthesize type I interferon upon TLR triggering. Mechanistically, we found that IFN-α-pDCs show increased IRF7 mRNA and protein upon TLR stimulation, but despite efficient nuclear IRF-7 translocation, type I IFN was not produced. Interestingly, Ifn-α6 promoter activity was blocked in the IFN-α-pDCs, suggesting a block of type I IFN transcription despite nuclear IRF-7 translocation. Taken together, triggering of TLR and of IFN-α/βR act independently to tightly limit systemic IFN-α production after IFNs treatment. All this reveals the complexity of the IFN-α-pDC interactions under normal and pathological conditions and stimulates further studies for identifying optimal modalities in either using these cytokines or controlling their production in melanoma patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5396. doi:1538-7445.AM2012-5396