Abstract
Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. Our observations on human samples indicated enhanced epidermal infiltration of CD8 T cells, and the pathogenesis of which appears to be dependent on IL-6 in the PD-1 signal blockade-induced psoriasis-like dermatitis. By using a murine model of imiquimod-induced psoriasis-like dermatitis, we further demonstrated that PD-1 deficiency accelerates skin inflammation with activated cytotoxic CD8 T cells into the epidermis, which engage in pathogenic cross-talk with keratinocytes resulting in production of IL-6. Moreover, genetically modified mice lacking PD-1 expression only on CD8 T cells developed accelerated dermatitis, moreover, blockade of IL-6 signaling by anti-IL-6 receptor antibody could ameliorate the dermatitis. Collectively, PD-1 signal blockade-induced psoriasis-like dermatitis is mediated by PD-1 signaling on CD8 T cells, and furthermore, IL-6 is likely to be a therapeutic target for the dermatitis.
Highlights
Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events including psoriasis-like dermatitis
We reported in our preliminary study that only increased serum levels of IL-6, but not those of IL-17A, interferon (IFN)γ and IL-8, correlated with the development of anti-PD-1 antibody-induced psoriasis-like dermatitis in patients with malignant melanoma[25]
A murine model of IMQ-induced psoriasislike dermatitis clearly demonstrated that PD-1 deficiency accelerates infiltration of epidermal CD8 T cells with enhanced IFN-γ production of inflamed skin, and IFN-γ-stimulated keratinocytes produced an IFN-γ-inducible chemokine (CXCL9) for recruitment of
Summary
Use of immune checkpoint inhibitors that target programmed cell death-1 (PD-1) can lead to various autoimmune-related adverse events (irAEs) including psoriasis-like dermatitis. High-dose and/or long-term use of systemic immunosuppressive therapies are required to control such irAEs23, potentially resulting in prolonged interruption of cancer treatment. These immunosuppressive therapies may abrogate the antitumor response by counteracting lymphocyte activation[20,24]. A recent American Society of Clinical Oncology guideline suggests that cutaneous irAEs are increasingly recognized as a contributing factor to treatment noncompliance, discontinuation, or dose modification[24] Such skin manifestations cause changes in appearance along with discomfort, which reduces patient quality of life and results in loss of treatment motivation. More than 18% (19 /103) of those cases were reportedly severe[27]
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