Contact with Cancer Cells Induces Inflammatory Pathways in Fibroblasts

Cancer-associated fibroblasts (CAF) can produce inflammatory substances that may contribute to resistance to anticancer therapies, including oncolytic-virus treatment. To investigate the mechanisms underlying CAFs' production of inflammatory modulators and their potential link to resistance to treatment with oncolytic viruses, Arwert, Milford, Rullan, and colleagues started by determining the results of contact between cancer cells and CAFs or fibroblasts from normal tissue. In normal tissues, direct contact between epithelial cells and fibroblasts is prevented by the basement membrane, but this barrier to interaction is disrupted in tumors. Direct coculture of cancer cells with fibroblasts led to induction of genes encoding cytokines and chemokines along with interferon-stimulated genes (ISG), all encoding inflammatory modulators. Among these, IFNB1, encoding interferon-β1, was rapidly upregulated in a subset of CAFs, triggering ISG transcription in both CAFs and cancer cells. The induction of IFNB1 and consequent upregulation of ISGs was dependent on interferon regulatory factor 3 (IRF3), a transcription factor involved in the innate-immune response to viral infection, which was found at elevated levels in nuclei of CAFs in contact with cancer cells. Interestingly, the IRF3 activation caused by cancer cell–CAF contact appeared to be dependent on cGAS–STING signaling, which is normally triggered by the presence of cytosolic DNA; this finding raised the question of how cell–cell contact would affect this pathway. Further experiments revealed small amounts of cytoplasmic material from cancer cells were transcytosed into CAFs upon direct cell–cell contact, providing a mechanism for the transfer of both cGAMP, the second messenger in cGAS–STING signaling, and cytosolic DNA fragments generated as a result of the genomic stress present in cancer cells. Importantly, the transcriptional programs triggered by activation of this pathway reduced the efficacy of oncolytic viruses in killing cancer cells in vitro and their suppression of tumor growth in vivo. In summary, this work provides an intricate characterization of the effects of cancer cell–CAF contact at the molecular scale and shows how this dynamic can interfere with the therapeutic effects of oncolytic viruses.

Arwert EN, Milford EL, Rullan A, Derzsi S, Hooper S, Kato T, et al. STING and IRF3 in stromal fibroblasts enable sensing of genomic stress in cancer cells to undermine oncolytic viral therapy. Nat Cell Biol 2020;22:758–66.

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