Skip to Content
Merck
  • STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy.

STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy.

Nature cell biology (2020-06-03)
Esther N Arwert, Emma L Milford, Antonio Rullan, Stefanie Derzsi, Steven Hooper, Takuya Kato, David Mansfield, Alan Melcher, Kevin J Harrington, Erik Sahai
ABSTRACT

Cancer-associated fibroblasts (CAFs) perform diverse roles and can modulate therapy responses1. The inflammatory environment within tumours also influences responses to many therapies, including the efficacy of oncolytic viruses2; however, the role of CAFs in this context remains unclear. Furthermore, little is known about the cell signalling triggered by heterotypic cancer cell-fibroblast contacts and about what activates fibroblasts to express inflammatory mediators1,3. Here, we show that direct contact between cancer cells and CAFs triggers the expression of a wide range of inflammatory modulators by fibroblasts. This is initiated following transcytosis of cytoplasm from cancer cells into fibroblasts, leading to the activation of STING and IRF3-mediated expression of interferon-β1 and other cytokines. Interferon-β1 then drives interferon-stimulated transcriptional programs in both cancer cells and stromal fibroblasts and ultimately undermines the efficacy of oncolytic viruses, both in vitro and in vivo. Further, targeting IRF3 solely in stromal fibroblasts restores oncolytic herpes simplex virus function.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Mowiol® 4-88, Mw ~31,000
Sigma-Aldrich
2-Mercaptoethanol, ≥99.0%
Sigma-Aldrich
Tonabersat, ≥98% (HPLC)
Sigma-Aldrich
Anti-phospho-Histone H2A.X (Ser139) Antibody, clone JBW301, clone JBW301, Upstate®, from mouse
Sigma-Aldrich
DAPI, for nucleic acid staining
Sigma-Aldrich
Anti-Fibronectin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Sigma-Aldrich
Triton X-100, laboratory grade
Sigma-Aldrich
Monoclonal Anti-Vimentin antibody produced in mouse, clone LN-6, ascites fluid
Sigma-Aldrich
Anti-β-Actin antibody, Mouse monoclonal, clone AC-15, purified from hybridoma cell culture
Sigma-Aldrich
Anti-DNA Antibody, double stranded, clone AE-2, clone AE-2, Chemicon®, from mouse