IFN‐γ‐induced PD‐L1 expression on human melanocytes is impaired in vitiligo

Abstract Mounting evidence shows that the PD‐1/PD‐L1 axis is involved in tumor immune evasion. This is demonstrated by anti‐PD‐1 antibodies that can reverse tumor‐associated PD‐L1 to functionally suppress anti‐tumor T‐cell responses. Since type I and II interferons are key regulators of PD‐L1 expression in melanoma cells and IFN‐γ‐producing CD8 + T cells and IFN‐α‐producing dendritic cells are abundant in vitiligo skin, we aimed to study the role of PD‐1/PD‐L1 signalling in melanocyte destruction in vitiligo. Moreover, impaired PD‐1/PD‐L1 function is observed in a variety of autoimmune diseases. It is, therefore, hypothesized that manipulating PD‐1/PD‐L1 signalling might have therapeutic potential in vitiligo. The PD‐1 + T cells were abundantly present in situ in perilesional vitiligo skin, but expression of PD‐L1 was limited and confined exclusively to dermal T cells. More specifically, neither melanocytes nor other epidermal skin cells expressed PD‐L1. Exposure to IFN‐γ, but also type I interferons, increased PD‐L1 expression in primary melanocytes and fibroblasts, derived from healthy donors. Primary human keratinocytes only showed increased PD‐L1 expression upon stimulation with IFN‐γ. More interestingly, melanocytes derived from non‐lesional vitiligo skin showed no PD‐L1 upregulation upon IFN‐γ exposure, while other skin cells displayed significant PD‐L1 expression after exposure. In a vitiligo skin explant model, incubation of non‐lesional vitiligo skin with activated (IFN‐γ‐producing) T cells from vitiligo lesions was previously described to induce melanocyte apoptosis. Although PD‐L1 expression was induced in epidermal cells in these explants, this induction was completely absent in melanocytes. The lack of PD‐L1 upregulation by melanocytes in the presence of IFN‐γ‐producing T cells shows that melanocytes lack protection against T‐cell attack during vitiligo pathogenesis. Manipulating PD‐1/PD‐L1 signalling may, therefore, be a therapeutic option for vitiligo patients.