Abstract
DNA-damaging cancer therapies induce interferon expression and stimulate the immune system, promoting therapy responses. The immune-activating STING (Stimulator of Interferon Genes) pathway is induced when DNA or double-stranded RNA (dsRNA) is detected in the cell cytoplasm, which can be caused by viral infection or by DNA damage following chemo- or radiotherapy. Here, we investigated the responses of cutaneous T-cell lymphoma (CTCL) cells to the clinically applied DNA crosslinking photochemotherapy (combination of 8–methoxypsoralen and UVA light; 8–MOP + UVA). We showed that this treatment evokes interferon expression and that the type III interferon IFNL1 is the major cytokine induced. IFNL1 upregulation is dependent on STING and on the cytoplasmic DNA sensor cyclic GMP-AMP synthase (cGAS). Furthermore, 8–MOP + UVA treatment induced the expression of genes in pathways involved in response to the tumor necrosis factor, innate immune system and acute inflammatory response. Notably, a subset of these genes was under control of the STING–IFNL1 pathway. In conclusion, our data connected DNA damage with immune system activation via the STING pathway and contributed to a better understanding of the effectiveness of photochemotherapy.
Highlights
Therapeutic modalities like chemo- and radiotherapy cause DNA damage and are toxic for fast-dividing cells
We identified four genes where 8–MOP + UVA induction was suppressed by interferon lambda 1 (IFNL1) depletion, suggesting that they remain under the control of IFNL1 (Figure 6A–D)
Stimulator of Interferon Genes (STING) pathway activation, activates the STING/cyclic GMP-AMP synthase (cGAS) pathway in cutaneous T-cell lymphoma (CTCL) cells. This activation results in a transcriptional response resulting in interferon expression, has previously been described both in malignant cells and in involving a plethora of genes, with IFNL1 being a major induced cytokine
Summary
Therapeutic modalities like chemo- and radiotherapy cause DNA damage and are toxic for fast-dividing cells. Therapeutic success cannot solely be accounted for by direct cytotoxicity. The eradication of cancer cells following DNA damaging therapeutics can further be attributed to stimulation of an anticancer immune response linked in part to the pattern recognition of cytoplasmic DNA [1,2,3,4]. Stimulator of Interferon Genes (STING) Pathway and Cancer. STING, aka transmembrane protein 173 (TMEM173), connects cellular DNA damage with the immune system response. Infection with DNA viruses, retroviruses or bacteria may result in the presence of cytosolic DNA, which acts as a danger signal and activates the immune response. Cytosolic DNA is detected in a sequence-independent manner by sensors such as cyclic GMP-AMP
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