使用免疫疗法（包括抑制点抑制剂）是治疗转移性黑色素瘤的有效方法。在免疫疗法过程中出现白癜风是一种特异性的免疫相关不良事件（irAE），被诊断为15%的患者，并与积极的临床反应相关。因此，对黑色素瘤患者在白癜风发生过程中的免疫细胞进行详细的特性描述，可以揭示同时介导irAE和抗肿瘤反应的免疫机制的见解。为了更好地理解这些方面，我们分析了接受抗编程细胞死亡蛋白（PD-1）抗体治疗的转移性黑色素瘤患者外周血T细胞亚群。为了深入了解与白癜风发生同时发生的抗肿瘤T细胞反应，我们分析了患有白癜风的黑色素瘤患者皮肤活检中的T细胞含量。此外，为了进一步特性化黑色素瘤患者白癜风皮损中的T细胞，我们对来自白癜风和同一患者的原发性黑色素瘤活检所得细胞的T细胞受体（TCR）进行了测序。在进行抗PD-1治疗期间对患者进行白癜风发展与否的分层显示，血液中CD8-粘膜相关不变T（MAIT），T辅助（h）17，自然杀伤（NK）CD56明亮以及调节性（T-reg）细胞的减少与白癜风发生有关。与发展白癜风的黑色素瘤患者中观察到的Th17细胞减少相一致，我们在白癜风皮损中发现了大量表达IL-17A的细胞，暗示Th17细胞可能从血液中迁移至自身免疫病变部位。有趣的是，除少数情况外，我们发现白癜风和原发性黑色素瘤病灶之间存在不同的TCR序列。相反，我们在白癜风和同一患者的转移组织中找到了共享的TCR序列。这些数据表明，针对正常黑色素细胞的T细胞反应，参与了白癜风的发生，通常不是通过重新激活渗透到原发性黑色素瘤中的特定T细胞克隆介导，而是可能由以转移性组织为靶的T细胞克隆引发。总体而言，我们的数据表明，抗PD-1疗法诱导了一种新的免疫反应，受到转移性细胞存在的刺激，并由不同的T细胞亚型组成，可能触发白癜风的发展和对转移性肿瘤的反应。 版权所有© 2023 Carbone, Capone, Guercio, Reddel, Silvestris, Lulli, Ramondino, Peluso, Quintarelli, Volpe和Failla。

Immunotherapy with checkpoint inhibitors is an efficient treatment for metastatic melanoma. Development of vitiligo upon immunotherapy represents a specific immune-related adverse event (irAE) diagnosed in 15% of patients and associated with a positive clinical response. Therefore, a detailed characterization of immune cells during vitiligo onset in melanoma patients would give insight into the immune mechanisms mediating both the irAE and the anti-tumor response.To better understand these aspects, we analyzed T cell subsets from peripheral blood of metastatic melanoma patients undergoing treatment with anti-programmed cell death protein (PD)-1 antibodies. To deeply characterize the antitumoral T cell response concomitant to vitiligo onset, we analyzed T cell content in skin biopsies collected from melanoma patients who developed vitiligo. Moreover, to further characterize T cells in vitiligo skin lesion of melanoma patients, we sequenced T cell receptor (TCR) of cells derived from biopsies of vitiligo and primary melanoma of the same patient.Stratification of patients for developing or not developing vitiligo during anti-PD-1 therapy revealed an association between blood reduction of CD8-mucosal associated invariant T (MAIT), T helper (h) 17, natural killer (NK) CD56bright, and T regulatory (T-reg) cells and vitiligo onset. Consistently with the observed blood reduction of Th17 cells in melanoma patients developing vitiligo during immunotherapy, we found high amount of IL-17A expressing cells in the vitiligo skin biopsy, suggesting a possible migration of Th17 cells from the blood into the autoimmune lesion. Interestingly, except for a few cases, we found different TCR sequences between vitiligo and primary melanoma lesions. In contrast, shared TCR sequences were identified between vitiligo and metastatic tissues of the same patient. These data indicate that T cell response against normal melanocytes, which is involved in vitiligo onset, is not typically mediated by reactivation of specific T cell clones infiltrating primary melanoma but may be elicited by T cell clones targeting metastatic tissues. Altogether, our data indicate that anti-PD-1 therapy induces a de novo immune response, stimulated by the presence of metastatic cells, and composed of different T cell subtypes, which may trigger the development of vitiligo and the response against metastatic tumor.Copyright © 2023 Carbone, Capone, Guercio, Reddel, Silvestris, Lulli, Ramondino, Peluso, Quintarelli, Volpe and Failla.