Anti-CTLA4 treatment reduces lymphedema risk through a systemic expansion of the FOXP3+ Treg population

Abstract Secondary lymphedema is a common sequel of oncologic surgery following lymphatic injury and presents a substantial global health burden for which no pharmacological treatment exists. The infiltration of the affected lymphedematous extremities with CD4+T-cells has been shown to influence lymphedema onset. Various approaches towards their manipulation have emerged as a promising strategy in lymphedema therapy. Here, we show that the modulation of CD4+FOXP3+ regulatory T-cells (Tregs) upon anti-CTLA4 treatment can protect against lymphedema development in melanoma patients and a mouse lymphedema model. A retrospective evaluation of a melanoma patients’ registry revealed that anti-CTLA4 reduces lymphedema risk compared to patients receiving only lymphadenectomy. Importantly, lymphedema tissue biopsies from human and mice presented an increased infiltration with CTLA4+ and Treg cells. To assess the underlying mechanism, anti-CTLA4 was used in the murine-tail lymphedema model, leading to a significant edema reduction and improvement of lymphatic function. The effect of the anti-CTLA4 treatment was attributed to the systemic expansion of Tregs, both in the animal model and in melanoma patients. The data from both, the pre-clinical and human studies indicating the protective effect of anti-CTLA4 against lymphedema, coupled with its anti-tumor properties, identify a promising candidate suitable for quick transition in the clinics. One Sentence Summary: Anti-CTLA4 treatment reduces lymphedema risk in melanoma patients and lymphedema development in a pre-clinical model via Treg cell modulation.