Adenovirus-mediated interferon-gamma transfer inhibits growth of transplanted HTLV-1 Tax tumors in mice.
Human T cell leukemia virus type 1 (HTLV-1) causes adult T cell leukemia (ATL), and the virus-encoded trans-activator, Tax, plays an important role in T cell transformation. In the HTLV-1 long terminal repeat (LTR)-Tax transgenic mouse model, Tax expression causes fibroblastic tumors. A tumor-derived cell line (B line) obtained from an explant of a Tax-transformed tumor, was established. This line expresses high levels of many cytokines as a consequence of Tax activation. However, the tumors are not immunogenic when transplanted into syngeneic mice. Because B line cells do not express the immunogenic cytokine interferon-gamma (IFN-gamma), a replication-defective adenoviral vector was used to deliver the IFN-gamma gene to tumor cells. The recombinant IFN-gamma adenovirus (IFN-gamma/Ad) can efficiently infect B line cells, resulting in high levels of IFN-gamma expression and secretion. Local secretion of IFN-gamma from B line cells caused both CD(4+)- and CD(8+)-positive T cell infiltration, and completely inhibited local tumor development in transplanted mice. Immunization with these cells significantly delayed tumor development after subsequent challenges of parental tumor cells. Expression of IFN-gamma in B cells also partially inhibited the highly expressed immune suppressive cytokine, transforming growth factor-beta 1 (TGF-beta 1). This system provides us with a valuable tumor immune therapy model to evaluate the effects of cytokines in induction or inhibition of specific antitumor immunity.
Xu
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Department of Molecular and Experimental Medicine, Scripps Research Institue, La Jolla, CA 92037, USA.
Dai
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Heidenreich
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Nerenberg
M I
MI
D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D015536:Down-Regulation; D005354:Fibrosarcoma / Q000628:therapy*; D015870:Gene Expression; D016356:Gene Products, tax / Q000235:genetics / Q000378:metabolism; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors; D015368:Human T-lymphotropic virus 1; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics* / Q000378:metabolism / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014611:Vaccination
D016356:Gene Products, tax; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma