Epidermal growth factor receptor inhibitors trigger a type I interferon response in human skin

Abstract

The Epidermal Growth Factor Receptor (EGFR) is centrally involved in the regulation of key processes of the epithelia, including cell proliferation, survival, differentiation, and also tumorigenesis. Humanized antibodies and small-molecule inhibitors targeting EGFR were developed to disrupt these functions in cancer cells and are currently used in the treatment of diverse metastatic epithelial cancers. By contrast, these drugs possess significant skin-specific toxic effects, comprising the establishment of a persistent inflammatory milieu. So far, the molecular mechanisms underlying these epiphenomena have been investigated rather poorly. Here we showed that keratinocytes respond to anti-EGFR drugs with the development of a type I interferon molecular signature. Upregulation of the transcription factor IRF1 is early implicated in the enhanced expression of interferon-kappa, leading to persistent activation of STAT1 and further amplification of downstream interferon-induced genes, including anti-viral effectors and chemokines. When anti-EGFR drugs are associated to TNF-α, whose expression is enhanced by the drugs themselves, all these molecular events undergo a dramatic enhancement by synergy mechanisms. Finally, high levels of interferon-kappa can be observed in epidermal keratinocytes and also in leukocytes infiltrating the upper dermis of cetuximab-driven skin lesions. Our data suggest that dysregulated activation of type I interferon innate immunity is implicated in the molecular processes triggered by anti-EGFR drugs and leading to persistent skin inflammation.

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

“…IFNκ is expressed by basal and parabasal keratinocytes, but it is downregulated in more differentiated layers of the epithelium 40 . Second, IFNκ is expressed to high levels in unstimulated, normal keratinocytes, while neither IFNβ nor IFNα is expressed in the absence of stimulation 254,270,275 . The fact that IFNκ is constitutively expressed positions it to serve an important surveillance role.…”

“…The fact that IFNκ is constitutively expressed positions it to serve an important surveillance role. Third, IFNκ is only weakly induced by stimuli that regulate other type I IFNs 40,254,270 . Other signals that may regulate IFNκ are unknown, except that it is readily induced by IFNγ 40 and upon EGFR inhibition through activation of IRF1 270 .…”

“…Overexpressed E5 can induce IFNβ by upregulating IRF1 expression 269 . On the other hand, E5 also promotes EGFR signaling, which inhibits IFN responses 270–273 (see below). Finally, E2 can transcriptionally suppresses Stimulator of interferon genes (STING), which transduces in cytoplasmic DNA signals to the IRF pathway 235,274 .…”

“…Inhibition of EGFR in keratinocytes grown in monolayer or in organotypic culture results in increased inflammatory and immune response genes, including IFN expression, NFκB signaling 415,416 . EGFR inhibition in patients causes increases in various chemokines and cytokines in the skin, including CCL2, CCL5, IL8, GM-CSF, and IFNκ 270,417,418 . EGFR can inhibit IRF1 activation, resulting in suppression of the IFN pathway and ISG synthesis, especially IFNκ 270,419–421 .…”

Search for New Type of Anticancer Drugs with High Tumor Specificity and Less Keratinocyte Toxicity

“…It is well known that administration of anticancer agents induces skin toxicity (1)(2)(3)(4)(5)(6)(7). This prompted us to re-evaluate the cytotoxicity and tumor specificity of anticancer drugs.…”