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TNF plays an essential role in tumor regression after adoptive transfer of perforin/IFN-gamma double knockout effector T cells

  1. Author:
    Poehlein, C. H.
    Hu, H. M.
    Yamada, J.
    Assmann, K.
    Alvord, W. G.
    Urba, W. J.
    Fox, B. A.

  2. Author Address

    Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Mol & Tumor Immunol, 4805 NE Gilsan St, Portland, OR 97213 USA Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Mol & Tumor Immunol, Portland, OR 97213 USA Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Clin Res, Portland, OR 97213 USA Oregon Hlth & Sci Univ, Oregon Grad Inst, Dept Biochem & Mol Biol, Portland, OR 97202 USA Oregon Hlth & Sci Univ, Dept Mol Microbiol & Immunol, Portland, OR 97202 USA Oregon Hlth & Sci Univ, Oregon Canc Ctr, Portland, OR 97202 USA NCI, Frederick Canc Res & Dev Ctr, Data Management Serv, Frederick, MD 21702 USA Fox BA Providence Portland Med Ctr, Earle A Chiles Res Inst, Robert W Franz Canc Res Ctr, Lab Mol & Tumor Immunol, 4805 NE Gilsan St, Portland, OR 97213 USA
    1. Year: 2003
  2. Journal: Journal of Immunology
    1. 170
    2. 4
    3. Pages: 2004-2013
  4. Type of Article: Article
  1. Abstract:

    We have recently shown that effector T cells (T-E) lacking either perforin or IFN-gamma are highly effective mediators of tumor regression. To rule out compensation by either mechanism, TE deficient in both perforin and IFN-gamma (perforin knockout (PKO)/IFN-gamma knockout (GKO)) were generated. The adoptive transfer of PKO/GKO T, mediated complete tumor regression and cured wild-type animals with established pulmonary metastases of the B16BL6-D5 (D5) melanoma cell line. PKO/GKO T-E also mediated tumor regression in D5 tumor-bearing PKO, GKO, or PKO/GKO recipients, although in PKO/GKO recipients efficacy was reduced. PKO/GKO T-E exhibited tumor-specific TNF-alpha production and cytotoxicity in a 24-h assay, which was blocked by the soluble TNFRII-human IgG fusion protein (TNFRII:Fc). Blocking TNF in vivo by administering soluble TNFR 11 fusion protein (TNFRII:Fc) significantly reduced the therapeutic efficacy of PKO/GKO, but not wild-type T-E. This study identifies perforin, IFN-gamma and TNF as a critical triad of effector molecules that characterize therapeutic antitumor T cells. These insights could be used to monitor and potentially tune the immune response to cancer vaccines.

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