Background:
Propranolol has been linked to improvement in melanoma outcomes, but the mechanism is unclear. It has known anti-vascular and lymphatic-stabilising properties via inhibition of SOX18 by the R(+)-enantiomer, but these have not been demonstrated in human lymph nodes. The MELPROP trial was designed to test whether short-course pre-operative propranolol could modulate lymph node architecture and transcriptional programmes in patients with melanoma undergoing sentinel lymph node biopsy (SLNB).
Methods:
MELPROP was a single-centre, prospectively recruited, double-blinded, randomised placebo-controlled trial in patients with stage IB-II cutaneous melanoma (T1b-T4c) scheduled for SLNB, with participants receiving propranolol 40 mg twice daily or placebo for up to three weeks before surgery. Sentinel lymph node (SLN) tissue from 16 patients underwent single-cell transcriptomic profiling. Propranolol-exposed vs. unexposed SLNs were compared for cell composition and transcriptional differences including beta-adrenergic, SOX18-mevalonate pathway (SOX18-MVP), and lymphangiogenesis-associated programmes.
Results:
The atlas resolved major lymphoid, myeloid, endothelial, and stromal compartments, with second-order annotation identifying diverse immune and vascular niche populations within melanoma-draining SLNs. Propranolol exposure did not significantly alter SLN cellular composition and did not alter beta-adrenergic signalling, nor SOX18-MVP or lymphangiogenesis pathways, including in a sensitivity analysis restricted to the high-exposure subset. Single-gene differential-expression effects were modest, including altered expression of MACROH2A2 globally, SCGB3A1 in T-cell populations, SCD5 in myeloid and dendritic compartments, NT5E/CD73 in B cells, and several dendritic- and vascular-associated genes such as CCL17, ADTRP, EPSTI1, GPIHBP1, SEC16B, and TMEM19.
Conclusions:
Short-course pre-operative propranolol did not induce remodelling of melanoma SLNs nor effect major transcriptional alteration, suggesting that any biological effect in this tissue is subtle, spatially restricted, or requires longer or higher exposure. Even so, this study generated the largest yet human single-cell atlas of melanoma-draining SLNs and identified candidate immune and endothelial transcriptional changes that merit further investigation.