Blockade of Hyaluronan Inhibits IL-2-Induced Vascular Leak Syndrome and Maintains Effectiveness of IL-2 Treatment for Metastatic Melanoma

Abstract

Vascular leak syndrome (VLS) is a life-threatening toxicity induced during IL-2 treatment of cancer patients. The mechanism of IL-2-induced VLS is still poorly understood. At present, there is no specific therapy for VLS. Previous studies from our laboratory demonstrated that hyaluronan (HA), a large glycosaminoglycan, abundant in the extracellular matrix and on the cell surface, caused a marked increase of IL-2-induced VLS in the lungs and liver of C57BL/6 mice. Conversely, blockade or knockout of its major receptor, CD44, resulted in a marked decrease of VLS, thereby suggesting a role for HA in VLS. In this study, we report a novel means to prevent IL-2-induced VLS by blocking endogenous HA with HA-specific binding peptide, Pep-1, a newly isolated peptide which specifically binds to soluble, cell-associated, and immobilized forms of HA. Our results demonstrated that blocking HA with Pep-1 dramatically inhibited IL-2-induced VLS in both normal mice as well as in mice bearing melanoma. Moreover, Pep-1 treatment maintained the effectiveness of IL-2 and prevented the metastasis of melanoma. IL-2-induced emigration of lymphocytes across the endothelium and cytotoxicity against tumor by lymphokine-activated killer cells were not affected by Pep-1. Instead, use of Pep-1 maintained endothelial integrity and reduced their apoptosis during IL-2-induced VLS. These data suggested that HA plays a critical role in regulating endothelial cell damage and induction of IL-2-mediated VLS. Also, blockade of HA using Pep-1 could constitute a novel therapeutic modality to prevent IL-2-mediated toxicity, thereby facilitating the effectiveness of high-dose IL-2 in the treatment of metastatic melanomas.