Mechanisms of dermatologic toxicities to immune checkpoint inhibitor cancer therapies.

The discovery of immune checkpoint inhibition (ICI) sparked a revolution in the era of targeted anticancer therapy. While monoclonal antibodies targeting the CTLA-4 and PD-1 axes have improved survival in patients with advanced cancers, these immunotherapies are associated with a wide spectrum of dermatologic immune-related adverse events (irAEs). Several publications have addressed the clinical and histopathologic classification of these skin-directed irAEs, their impact on antitumor immunity and survival, and the critical role of supportive oncologic dermatology in their management. Here, we review the current understanding of the mechanistic drivers of immune-related skin toxicities with a focus on inflammatory, immunobullous, 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 non-cutaneous irAEs and potential overlap with cutaneous irAEs, techniques to study differences in immune-related versus de novo skin reactions, and how treatment of these adverse events impacts cancer treatment, patient quality of life, and overall survival. An improved understanding of the mechanistic basis of cutaneous irAEs will allow us to develop and utilize 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 abrogating anti-tumor effect of ICIs