Wnt inhibition activates Interferon Stimulated Gene expression by alleviating epigenetic repression of endogenous retroviruses

To identify mechanisms through which WNT signaling limits anti-tumor immunity, we examined the response to WNT inhibition in a variety of human cancer cell lines that harbor distinct WNT pathway mutations. Our data show that inhibition of WNT signaling leads to activation of the TBK1/IRF3 dsRNA-sensing pathway and expression of interferon-stimulated genes (ISGs), independently of IFNa/JAK/STAT signaling.

Mechanistically, we show that WNT inhibition leads to increased chromatin accessibility at genomic loci harboring endogenous retroviruses (ERVs), resulting in ERV re-expression and activation of the dsRNA response. Increased ISG expression following WNT inhibition does not involve decreased MAP kinase signaling and therefore differs from reports documenting ISG induction in response to inhibition of other oncogenic pathways.