The development of new vascular structures is a pre-requisite for melanoma growth and spread. Previous studies have shown that tumour vessels arise from endovascular progenitor (EVP) forming transit amplifying (TA) and then differentiated (D) endothelial cells in various melanoma models. RNA-seq of EVPs as compared to D cells pointed to IL-6/JAK/STAT signalling as significantly upregulated in the EVP. This was validated using P-STAT3 staining on sorted cells. Of importance IL6Ra was upregulated substantially in tumour EVPs but not in other vascular beds such as the aorta. We next sought to specifically target EVP activity. Anti-IL6Rα and Ruxolitinib blocked JAK/STAT signalling, significantly reducing EVP infiltration into the tumour. Importantly, IL6Rα treatment caused a reduction in tumour size. Surprisingly, leading anti-angiogenic, Anti-VEGF-A did not affect EVP function. In HCMel12 metastatic model of melanoma injected subcutaneously, IL6Rα inhibition reduced EVP infiltrate into primary tumours. Neoadjuvant treatment with anti-mIL6Rα antibodies significantly reduced the number of metastatic nodules and size of nodules, confirmed by micro-CT imaging and subsequent H&E staining of murine lung tissue. Of importance, IL6Rα inhibition significantly reduced neutrophil and macrophage infiltration suggesting that part of the observed benefit emanates from anti-tumour immunity. Further, coupling Anti-VEGF-A and IL6Rα demonstrated no synergistic effects, in fact, IL6Rα monotherapy presented the lowest disease burden. In conclusion, IL6 signalling is a key regulator of endovascular progenitor ability to form vessels and regulate immune infiltration and tumour metastases.

ESDR258 - Interleukin 6 signalling in endovascular progenitors is a driver of melanoma vascularisation and metastasis

50th Annual Meeting of the European Society for Dermatological Research. VIRTUAL MEETING