Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• International journal of cancer, 2021-05, Vol.148 (9), p.2321-2334

Ort / Verlag

Hoboken, USA: John Wiley & Sons, Inc

Erscheinungsjahr

2021

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. What's new? The ability of oncolytic viruses to exploit tumor‐induced defects in antiviral responses suggests their potential to efficiently target definite subsets of melanomas, yet these should be defined. Here, the authors show that STAT1 is at the center of a tumor signature involving genes that mediate antiviral and immune activation responses. Using a murine melanoma model and a novel oncolytic virus, EHDV‐TAU, they identify epigenetic silencing as contributing to the underexpression of antiviral genes. Moreover, they demonstrate the potential of EHDV‐TAU to exploit this molecular landscape for effective oncolysis and immune stimulation.