title: IL-15 deficient tax mice reveal a role for IL-1α in tumor immunity.
abstract: IL-15 is recognized as a promising candidate for tumor immunotherapy and has been described as both a promoter of cancer and a promoter of anti-cancer immunity. IL-15 was discovered in cells transformed by HTLV-1, the etiologic agent of adult T cell leukemia/lymphoma (ATL) and the human retrovirus that carries the Tax oncogene. We have developed the TAX-LUC mouse model of ATL in which Tax expression drives both malignant transformation and luciferase expression, enabling non-invasive imaging of tumorigenesis in real time. To identify the role of IL-15 in spontaneous development of lymphoma in vivo, an IL-15(-/-) TAX-LUC strain was developed and examined. The absence of IL-15 resulted in aggressive tumor growth and accelerated mortality and demonstrated that IL-15 was not required for Tax-mediated lymphoma but was essential for anti-tumor immunity. Further analysis revealed a unique transcriptional profile in tumor cells that arise in the absence of IL-15 that included a significant increase in the expression of IL-1α and IL-1α-regulated cytokines. Moreover, anti-IL-1α antibodies and an IL-1 receptor antagonist (Anakinra) were used to interrogate the potential of IL-1α targeted therapies in this model. Taken together, these findings identify IL-15 and IL-1α as therapeutic targets in lymphoma.
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Rauch
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: John C
authors.initials: JC
authors.lastname: Harding
authors.affiliation: Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, Saint Louis, Missouri, United States of America.
authors.forename: Lee
authors.initials: L
authors.lastname: Ratner
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology*; D016356:Gene Products, tax / Q000235:genetics / Q000276:immunology; D017930:Genes, Reporter; D015490:HTLV-I Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D015368:Human T-lymphotropic virus 1 / Q000276:immunology; D007113:Immunity, Innate; D053590:Interleukin 1 Receptor Antagonist Protein / Q000494:pharmacology; D019409:Interleukin-15 / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D053582:Interleukin-1alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000821:virology; D008156:Luciferases / Q000235:genetics / Q000276:immunology; D051379:Mice; D057054:Molecular Imaging; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
chemical_list: D016356:Gene Products, tax; D053590:Interleukin 1 Receptor Antagonist Protein; D019409:Interleukin-15; D053582:Interleukin-1alpha; C514970:tax protein, Human T-lymphotrophic virus 1; D008156:Luciferases