Introduction:
Cutaneous immune-related adverse events (cirAEs) are the most common toxic effects associated with immune checkpoint inhibitors (ICIs) in melanoma treatment. Despite its prevalence, the baseline immune features associated with cirAE development remain unclear. This study characterises the incidence, severity, and outcomes of cirAEs in ICI-treated patients and investigates baseline peripheral immune features associated with their development.
Methods:
We performed a secondary analysis of clinical and biospecimen data from melanoma patients initiating ICI at a tertiary centre in Brisbane, between August 2021 and February 2023. Baseline peripheral blood samples underwent immunophenotyping using spectral flow cytometry with analysis of 110 functional, activation, and inhibitory markers. cirAEs were assessed retrospectively from clinical records. Incidence, severity, and phenotype of cirAEs were identified. Baseline immune profiles were analysed to explore associations with cirAE development.
Results:
The study identified 32 eligible patients, of whom 17 (53%) developed a cirAE. Most cirAEs were low grade, comprising 71% (n=12) Grade 1, 24% (n=4) Grade 2, and 6% (n=1) Grade 3 events. The most frequent phenotypes were non-specific rash (35%, n=6) and pruritus (18%, n=3), followed by lichenoid (12%, n=2), eczematous (12%, n=2), and psoriasiform (12%, n=2) eruptions. Patients who developed cirAEs demonstrated a trend toward improved survival compared with those without irAEs (log-rank p=0.06). Analysis of baseline characteristics showed no significant associations between cirAE and ICI regimen, age, sex, body mass index, or ethnicity (p>0.05). Notably, baseline immune profiling demonstrated increased expression of inhibitory immune checkpoint Lymphocyte Activation Gene-3 (LAG-3) on dendritic cell subsets in patients with no cirAE (p<0.05).
Conclusion:
cirAEs were common, predominantly mild with a trend toward improved survival in melanoma immunotherapy. Increased expression of LAG-3, an inhibitory immune checkpoint involved in attenuating immune activation, may reflect a more regulated immune state in patients with no cirAEs. Conversely, patients with less inhibitory immune regulation may be more susceptible to cutaneous toxicity, but may also exhibit stronger anti-tumour immune activity and hence better survival. These findings support the concept that cirAEs may serve as a clinically accessible marker of effective immune engagement and highlight the potential role of baseline immune profiling in toxicity risk stratification.