Department of Dermatology and Netherlands Institute for Pigment Disorders, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Cancer Center Amsterdam, Amsterdam Infection & Immunity Institute, Amsterdam, The Netherlands.
ISA Pharmaceuticals, Leiden, The Netherlands.
Exp Dermatol. 2022 Apr;31(4):556-566. doi: 10.1111/exd.14500. Epub 2021 Nov 17.
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.
越来越多的证据表明 PD-1/PD-L1 轴参与肿瘤免疫逃逸。这表现在抗 PD-1 抗体可以逆转肿瘤相关的 PD-L1，从而在功能上抑制抗肿瘤 T 细胞反应。由于 I 型和 II 型干扰素是黑色素瘤细胞和 IFN-γ 产生的 CD8 T 细胞以及 IFN-α 产生的树突状细胞中 PD-L1 表达的关键调节剂，并且白癜风皮肤中富含 IFN-α 产生的树突状细胞，我们旨在研究 PD-1/PD-L1 信号在白癜风中黑素细胞破坏中的作用。此外，在多种自身免疫性疾病中观察到 PD-1/PD-L1 功能受损。因此，假设操纵 PD-1/PD-L1 信号可能具有治疗白癜风的潜力。PD-1 T 细胞在病变周围白癜风皮肤中大量存在，但 PD-L1 的表达有限，仅限于真皮 T 细胞。更具体地说，黑色素细胞和其他表皮皮肤细胞均不表达 PD-L1。来自健康供体的原代黑色素细胞和成纤维细胞在暴露于 IFN-γ时，其 PD-L1 表达增加。原代人角质形成细胞仅在受到 IFN-γ刺激时才表现出 PD-L1 表达增加。更有趣的是，来自非病变性白癜风皮肤的黑素细胞在暴露于 IFN-γ时没有表现出 PD-L1 上调，而其他皮肤细胞在暴露于 IFN-γ后显示出明显的 PD-L1 表达。在白癜风皮肤外植体模型中，先前已描述过将来自白癜风病变的活化（IFN-γ产生）T 细胞孵育非病变性白癜风皮肤，以诱导黑素细胞凋亡。尽管在这些外植体中的表皮细胞中诱导了 PD-L1 表达，但在黑素细胞中则完全没有诱导。在存在 IFN-γ产生的 T 细胞的情况下，黑素细胞缺乏 PD-L1 上调表明在白癜风发病机制中黑素细胞缺乏对 T 细胞攻击的保护。因此，操纵 PD-1/PD-L1 信号可能是白癜风患者的一种治疗选择。
