Mechanisms of dermatological toxicities to immune checkpoint inhibitor cancer therapies

Abstract

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.

Inflammation of actinic keratosis from chemotherapy in a relapsed multiple myeloma patient

“…It may also represent a form of radiation recall, where a chemotherapeutic agent induces an inflammatory reaction in a site previously exposed to radiation, possibly solar radiation in this case 8. Although the inflammation of AK from immune checkpoint inhibitors has not been specifically reported, they can potentially lead to such manifestations through diversification of T-lymphocyte and B-lymphocyte populations and subsequent skin damage mediated by inflammatory cytokines and autoantibodies 11. Non-immune checkpoint inhibitor monoclonal antibody-based cancer therapies can also lead to inflamed AK by coexpression of their targets on keratinocytes 12.…”

Immunotherapy for Melanoma: The Significance of Immune Checkpoint Inhibitors for the Treatment of Advanced Melanoma

“…As described above, ICIs such as anti-PD1 Abs and anti-CTLA4 Abs have become anchor drugs in the treatment of advanced melanoma [ 1 , 2 , 5 ] ( Table 1 ). ICIs significantly prolong survival in patients with metastatic melanoma [ 1 , 2 , 13 ], but the associated risk of irAEs is an important consideration [ 46 , 47 , 48 ]. Among such irAEs, dermatological toxicities are among the most common, well-known and earliest onset irAEs [ 46 , 47 , 48 ]; however, especially in clinical studies, dermatological toxicities are categorized as “skin eruption”, and they were not further described.…”

“…ICIs significantly prolong survival in patients with metastatic melanoma [ 1 , 2 , 13 ], but the associated risk of irAEs is an important consideration [ 46 , 47 , 48 ]. Among such irAEs, dermatological toxicities are among the most common, well-known and earliest onset irAEs [ 46 , 47 , 48 ]; however, especially in clinical studies, dermatological toxicities are categorized as “skin eruption”, and they were not further described. Since cutaneous irAEs could present with various manifestations, and since the treatment for these cutaneous irAEs is different for each phenotype [ 46 , 47 ], the classification of cutaneous irAEs is important for the safe use of ICIs.…”

“…Among such irAEs, dermatological toxicities are among the most common, well-known and earliest onset irAEs [ 46 , 47 , 48 ]; however, especially in clinical studies, dermatological toxicities are categorized as “skin eruption”, and they were not further described. Since cutaneous irAEs could present with various manifestations, and since the treatment for these cutaneous irAEs is different for each phenotype [ 46 , 47 ], the classification of cutaneous irAEs is important for the safe use of ICIs. According to previous reports [ 46 , 47 , 48 ], cutaneous irAEs are roughly classified as follows: (1) enhancement of other inflammatory skin diseases (e.g., drug eruption, psoriasis, lichen planus); (2) induction of substantial autoimmune skin disease (e.g., bullous pemphigoid); (3) melanocytic skin reaction (e.g., vitiligo).…”

“…The most common subtypes of skin toxicity caused by ICIs are maculopapular rashes and a lichen planus-like lichenoid skin reaction [ 46 , 47 ]. The incidence rate of maculopapular rashes after anti-PD-1 Abs treatment is 24%, which may include pre-symptoms of other skin inflammatory irAEs [ 49 ].…”