β2‐adrenergic receptor expression in patients receiving bevacizumab therapy for metastatic melanoma

Abstract Background Vascular endothelial growth factor (VEGF) was initially known as vascular permeability factor and identified as a driver of tumour angiogenesis. Recently, its role in supporting an immunosuppressive tumour microenvironment was demonstrated, and anti‐VEGF treatment combined with immune checkpoint blockade is currently investigated. Further, beta‐adrenergic signalling as a modifier of cancer hallmarks like immune response, angiogenesis and metastasis gained increased attention during past years. Methods Focusing on the aspect of immunosuppression in upregulated beta‐adrenergic signalling, we investigated predictive markers in patients with metastatic melanoma who received bevacizumab monotherapy, a specific VEGF‐A binding antibody. We explored the expression of beta‐2 adrenergic receptor (β2‐AR), interleukin 6‐receptor (IL6‐R), cyclooxygenase 2 (COX2) and VEGF‐A by immunohistochemistry in melanoma to assess the correlation between these proteins in melanoma cells and response to treatment. Results Strong β2‐AR expression in metastases was associated with clinical benefit of bevacizumab. Furthermore, expression of the latter was positively linked to expression of VEGF‐A and COX2. β2‐AR expression in melanoma metastasis appears to distinguish a subgroup of patients that might benefit from anti‐VEGF treatment. Conclusion Our results strengthen further exploration of anti‐VEGF therapy in combination with immune checkpoint blockade in clinical studies and the investigation of β2‐AR as predictive marker.