CCR4-expressing T cell tumors can be specifically controlled via delivery of toxins to chemokine receptors.
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.
Baatar
Dolgor
D
Laboratory of Immunology, Gerontology Research Center, National Institute on Aging, Baltimore, MD 21224, USA.
Olkhanud
Purevdorj
P
Newton
Dianne
D
Sumitomo
Kenya
K
Biragyn
Arya
A
D036002:ADP Ribose Transferases / Q000235:genetics / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D001427:Bacterial Toxins / Q000235:genetics / Q000633:toxicity; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D045744:Cell Line, Tumor; D054414:Chemokine CCL17; D019742:Chemokines, CC / Q000008:administration & dosage / Q000235:genetics / Q000633:toxicity; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D047208:Eosinophil-Derived Neurotoxin / Q000235:genetics / Q000633:toxicity; D005098:Exotoxins / Q000235:genetics / Q000633:toxicity; D005260:Female; D006801:Humans; D000922:Immunotoxins / Q000235:genetics / Q000633:toxicity*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D054398:Receptors, CCR4; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000378:metabolism*; D014764:Viral Proteins / Q000235:genetics / Q000633:toxicity; D037521:Virulence Factors / Q000235:genetics / Q000633:toxicity; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D054414:Chemokine CCL17; D019742:Chemokines, CC; D047208:Eosinophil-Derived Neurotoxin; D005098:Exotoxins; D000922:Immunotoxins; D054398:Receptors, CCR4; D019707:Receptors, Chemokine; D014764:Viral Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C515354:CCR4 protein, human; C499538:Ccl17 protein, mouse; C515355:Ccr4 protein, mouse; C435144:MC148 protein, poxvirus molluscum contagiosum