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CCR4-Expressing T Cell Tumors Can Be Specifically Controlled via Delivery of Toxins to Chemokine Receptors¹

Dolgor Baatar^*, Purevdorj Olkhanud^*, Dianne Newton, Kenya Sumitomo^* and Arya Biragyn^2,*

^* Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224; and Department of Microbiology, SAIC-Frederick, National Cancer Institute, Frederick, MD 21702

Expression of chemokine receptors by tumors, specifically CCR4 on cutaneous T cell lymphomas, is often associated with a poor disease outcome. To test the hypothesis that chemokine receptor-expressing tumors can be successfully controlled by delivering toxins through their chemokine receptors, we have generated fusion proteins designated chemotoxins: chemokines fused with toxic moieties that are nontoxic unless delivered into the cell cytosol. We demonstrate that chemokines fused with human RNase eosinophil-derived neurotoxin or with a truncated fragment of Pseudomonas exotoxin 38 are able to specifically kill tumors in vitro upon internalization through their respective chemokine receptors. Moreover, treatment with the thymus and activation-regulated chemokine (CCL17)-expressing chemotoxin efficiently eradicated CCR4-expressing cutaneous T cell lymphoma/leukemia established in NOD-SCID mice. Taken together, this work represents a novel concept that may allow control of growth and dissemination of tumors that use chemokine receptors to metastasize and circumvent immunosurveillance.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This research was supported by the Intramural Research Program of the National Institute on Aging, National Institutes of Health.

² Address correspondence and reprint requests to Dr. Arya Biragyn, Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Box 21, Baltimore, MD 21224. E-mail address: biragyna{at}mail.nih.gov

³ Abbreviations used in this paper: ATLL, adult T cell leukemia/lymphoma; CTACK, cutaneous T cell-attracting chemokine; EDN, eosinophil-derived neurotoxin; HEK, human embryonic kidney; NHL, non-Hodgkin’s lymphoma; OFA, oncofetal Ag; PE38, Pseudomonas exotoxin 38; TARC, thymus and activation-regulated chemokine; Tregs, T regulatory cells.

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