Constitutive low expression of antiviral effectors sensitizes melanoma cells to a novel oncolytic virus

Sarah Dellac, Hamutal Ben-Dov, Ayala Raanan, Hanna Saleem, Rachel Zamostiano, Rinat Semyatich, Sara Lavi, Isaac P. Witz, Eran Bacharach, Marcelo Ehrlich

Research output: Contribution to journalArticlepeer-review

Abstract

STAT1 is a critical effector and a target gene of interferon (IFN) signaling, and thus a central mediator of antiviral responses. As both a mediator and a target of IFN signals, STAT1 expression reports on, and determines IFN activity. Gene expression analyses of melanoma patient samples revealed varied levels of STAT1 expression, which highly correlated with expression of >700 genes. The ability of oncolytic viruses to exploit tumor-induced defects to antiviral responses suggests that oncolytic viruses may efficiently target a subset of melanomas, yet these should be defined. We modeled this scenario with murine B16F10 melanomas, immortalized skin fibroblasts as controls and a novel oncolytic virus, EHDV-TAU. In B16F10 cells, constitutive low expression of STAT1 and its target genes, which included intracellular pattern recognition receptors (PRRs), correlated with their inability to mount IFN-based antiviral responses upon EHDV-TAU challenge, and with potency of EHDV-TAU-induced oncolysis. This underexpression of interferon stimulated genes (ISGs) and PRRs, and the inability of EHDV-TAU to induce their expression, were reversed by epigenetic modifiers, suggesting epigenetic silencing as a basis for their underexpression. Despite their inability to mount IFN/STAT-based responses upon viral infection, EHDV-TAU infected B16F10 cells secreted immune-stimulatory chemokines. Accordingly, in vivo, EHDV-TAU enhanced intratumoral infiltration of cytotoxic T-cells and reduced growth of local and distant tumors. We propose that “STAT1 signatures” should guide melanoma virotherapy treatments, and that oncolytic viruses such as EHDV-TAU have the potential to exploit the cellular context of low-STAT1 tumors.

Original languageEnglish
Pages (from-to)2321-2334
Number of pages14
JournalInternational Journal of Cancer
Volume148
Issue number9
DOIs
StatePublished - 1 May 2021

Keywords

  • Epizootic Hemorrhagic Disease Virus
  • STAT1
  • antiviral signaling
  • epigenetic regulation
  • interferon
  • melanoma
  • pattern recognition receptors
  • viral oncolysis

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