Department of Internal Medicine, Providence Portland Medical Center, Portland, OR, USA.
Medical Scientist Training Program, Baylor College of Medicine, Houston, TX, USA.
Clin Exp Dermatol. 2022 Nov;47(11):1928-1942. doi: 10.1111/ced.15332. Epub 2022 Sep 11.
The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. However, although monoclonal antibodies targeting the cytotoxic T-lymphocyte antigen-4 and programmed death-1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatological immune-related adverse events (irAEs), ranging from mild to life-threatening. Several publications have addressed the clinical and histopathological classification of these skin-directed irAEs, their impact on anti-tumour immunity and survival, and the critical role of supportive oncological dermatology in their management. In this paper, we review the current understanding of the mechanistic drivers of immune-related skin toxicities with a focus on inflammatory, immunobullous and melanocyte/pigment-related reactions. We detail the specific immune-based mechanisms that may underlie different cutaneous reactions. We also discuss potential mechanisms as they relate to extracutaneous irAEs and the lessons learned from these, the potential overlap with cutaneous irAEs, techniques to study differences in immune-related vs. de novo skin reactions, and how treatment of these AEs impacts cancer treatment, patient quality of life and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow clinicians to develop and use blood-based biomarkers that could help ultimately predict onset and/or severity of these irAEs, and to implement rational mechanistic-based treatment strategies that are targeted to the irAEs while potentially avoiding reducing the anti-tumour effect of ICIs.
免疫检查点抑制（ICI）的发现引发了靶向抗癌治疗时代的革命。然而，尽管针对细胞毒性 T 淋巴细胞抗原-4 和程序性死亡-1 轴的单克隆抗体提高了晚期癌症患者的生存率，但这些免疫疗法与广泛的皮肤科免疫相关不良事件（irAEs）相关，从轻到危及生命不等。有几篇出版物涉及这些针对皮肤的 irAEs 的临床和组织病理学分类、它们对抗肿瘤免疫和生存的影响，以及支持性肿瘤皮肤科在其管理中的关键作用。在本文中，我们回顾了目前对免疫相关皮肤毒性的机制驱动因素的理解，重点关注炎症、免疫性大疱病和黑素细胞/色素相关反应。我们详细介绍了可能是不同皮肤反应基础的特定免疫机制。我们还讨论了与皮肤外 irAEs 相关的潜在机制以及从中吸取的教训、与皮肤 irAEs 的潜在重叠、研究免疫相关与新发皮肤反应差异的技术，以及这些不良反应的治疗如何影响癌症治疗、患者生活质量和总体生存率。对皮肤 irAEs 的机制基础的更深入了解将使临床医生能够开发和使用基于血液的生物标志物，这些标志物最终可能有助于预测这些 irAEs 的发生和/或严重程度，并实施针对 irAEs 的合理机制治疗策略，同时有可能避免降低 ICI 的抗肿瘤作用。
