Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma

Lymphotoxin a (LTa) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTa in situ and that LTa expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTa functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTa and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTa plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease.