Adenovirus-Mediated Interferon-γTransfer Inhibits Growth of Transplanted HTLV-1 Tax Tumors in Mice

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Abstract
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-γ (IFN-γ), a replication-defective adenoviral vector was used to deliver the IFN-γ gene to tumor cells. The recombinant IFN-γ adenovirus (IFN-γ/Ad) can efficiently infect B line cells, resulting in high levels of IFN-γ expression and secretion. Local secretion of IFN-γ from B line cells caused both CD4+- and CD8+-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-γ in B cells also partially inhibited the highly expressed immune suppressive cytokine, transforming growth factor-β1 (TGF-β1). 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. Human T cell leukemia virus type 1 (HTLV-1) Tax gene expression in transgenic mice causes fibroblastic tumors. A tumor-derived cell line derived from these mice expresses many cytokines other than interferon-γ (IFN-γ), but is not immunogenic. A replication-defective adenovirus was used to direct expression of the IFN-γ gene in tumor cells. Local secretion of IFN-γ caused both CD4+ and CD8+ T cell infiltration, partial inhibition of TGF-β, and completely inhibited local tumor development in transplanted mice. Immunization with these cells significantly delayed tumor development after parental tumor cell challenges.

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