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TRAIL-coated leukocytes that kill cancer cells in the circulation

Significance This paper describes a unique approach to target and kill cancer cells in the bloodstream, in which the extensive surface area of circulating leukocytes is used to display the cancer-specific TNF-related apoptosis inducing ligand (TRAIL) and E-selectin adhesion receptor to the surrounding fluid. The approach is inspired by the cytotoxic activity of natural killer cells and is quite effective at killing cancer cells both in vitro with human blood samples and in mouse blood circulation. The mechanism is surprising and unexpected in that this repurposing of leukocytes in flowing blood is more effective than directly targeting the cancer cells with liposomes or soluble protein. Metastasis through the bloodstream contributes to poor prognosis in many types of cancer. Mounting evidence implicates selectin-based adhesive interactions between cancer cells and the blood vessel wall as facilitating this process, in a manner similar to leukocyte trafficking during inflammation. Here, we describe a unique approach to target and kill colon and prostate cancer cells in the blood that causes circulating leukocytes to present the cancer-specific TNF-related apoptosis inducing ligand (TRAIL) on their surface along with E-selectin adhesion receptor. This approach, demonstrated in vitro with human blood and also in mice, mimics the cytotoxic activity of natural killer cells and increases the surface area available for delivery of the receptor-mediated signal. The resulting “unnatural killer cells” hold promise as an effective means to neutralize circulating tumor cells that enter blood with the potential to form new metastases.