Interleukin-6 and interferon-α signaling via JAK1-STAT differentially regulate oncolytic versus cytoprotective antiviral states

Oded Danziger, Tal Pupko, Eran Bacharach*, Marcelo Ehrlich

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Malignancy-induced alterations to cytokine signaling in tumor cells differentially regulate their interactions with the immune system and oncolytic viruses. The abundance of inflammatory cytokines in the tumor microenvironment suggests that such signaling plays key roles in tumor development and therapy efficacy. The JAK-STAT axis transduces signals of interleukin-6 (IL-6) and interferons (IFNs), mediates antiviral responses, and is frequently altered in prostate cancer (PCa) cells. However, how activation of JAK-STAT signaling with different cytokines regulates interactions between oncolytic viruses and PCa cells is not known. Here, we employ LNCaP PCa cells, expressing (or not) JAK1, activated (or not) with IFNs (α or γ) or IL-6, and infected with RNA viruses of different oncolytic potential (EHDV-TAU, hMPV-GFP, or HIV-GFP) to address this matter. We show that in JAK1-expressing cells, IL-6 sensitized PCa cells to viral cell death in the presence or absence of productive infection, with dependence on virus employed. Contrastingly, IFNα induced a cytoprotective antiviral state. Biochemical and genetic (knockout) analyses revealed dependency of antiviral state or cytoprotection on STAT1 or STAT2 activation, respectively. In IL-6-treated cells, STAT3 expression was required for anti-proliferative signaling. Quantitative proteomics (SILAC) revealed a core repertoire of antiviral IFN-stimulated genes, induced by IL-6 or IFNs. Oncolysis in the absence of productive infection, induced by IL-6, correlated with reduction in regulators of cell cycle and metabolism. These results call for matching the viral features of the oncolytic agent, the malignancy-induced genetic-epigenetic alterations to JAK/STAT signaling and the cytokine composition of the tumor microenvironment for efficient oncolytic virotherapy.

Original languageEnglish
Article number94
JournalFrontiers in Immunology
Issue numberJAN
StatePublished - 30 Jan 2018


FundersFunder number
Erasmus Medical Centre
Hebrew University of Jerusalem
Israel Cancer Association20160113
Israel Science Foundation2427/16, 1824/13
Technion-Israel Institute of Technology


    • Epizootic hemorrhagic disease virus
    • Interferon
    • Interleukin-6
    • JAK1
    • Prostate cancer
    • STAT1
    • STAT3
    • Viral oncolysis


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