The microenvironment of ulcerated acral melanoma is characterised by an inflammatory milieu and an enhanced humoral immune response

Acral melanoma (AM) is a distinct and understudied subtype of melanoma that is reported to represent the majority of melanoma diagnoses in various Latin American, African and Asian countries. Patients with ulcerated AM diagnoses face a worse prognosis and increased risk of recurrence. While tumour ulceration has been shown to influence therapy response in cutaneous melanoma patients, the clinical and molecular traits of AM tumours remain poorly understood. In this study, we performed transcriptomic profiling of 59 AM samples and proteomic analysis of 45 AM samples from patients with extensively annotated clinical information. Our analysis revealed immunological differences in ulcerated tumours, including a significant upregulation of processes related to humoral immunity and markers for macrophages/monocytes, alongside a downregulation of keratins, epidermis-associated processes and cell adhesion. Notably, ulcerated tumours exhibited disruption of tight junctions and desmosomes, potentially explaining their compromised tissue integrity. We identified a significant increase of plasma cells, M0 macrophages and eosinophils within the ulcerated tumour microenvironment, suggesting that inflammation and infection might accompany these lesions. Moreover, fibronectin, CD8, PD-1, CD14 and CD68 protein levels were useful in distinguishing between ulcerated and non-ulcerated samples using a random forest classifier. These findings indicate that persistent inflammation and dysregulated immune responses characterise ulcerated AM, potentially offering new avenues for targeted therapeutic interventions in this aggressive melanoma subtype.