| Abstract: |
Transforming growth factor β (TGF-β), a pleiotropic cytokine that regulates cell growth and differentiation, is secreted by many human tumors and markedly inhibits tumor-specific cellular immunity. Tumors can avoid the differentiating and apoptotic effects of TGF-β by expressing a nonfunctional TGF-β receptor. We have determined whether this immune evasion strategy can be manipulated to shield tumor-specific cytotoxic T lymphocytes (CTLs) from the inhibitory effects of tumor-derived TGF-β. As our model we used Epstein-Barr virus (EBV)-specific CTLs that are infused as treatment for EBV-positive Hodgkin disease but that are vulnerable to the TGF-β produced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGF-β type II receptor HATGF-βRII-Δcyt. HATGF-βRII-Δcyt- but not green fluorescence protein (eGFP)-transduced CTLs was resistant to the antiproliferative and anticytotoxic effects of exogenous TGF-β. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGF-β receptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGF-βRII-Δcyt-transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGF-βRII-Δcyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGF-βRII-Δcyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-β-secreting tumors and may be of value in treatment of these diseases. © 2002 by The American Society of Hematology. |
| Keywords: |
signal transduction; controlled study; protein expression; protein phosphorylation; unclassified drug; human cell; mutation; dna-binding proteins; cell proliferation; phenotype; cell survival; cell function; cancer immunotherapy; gene expression; cell growth; smad protein; smad2 protein; transforming growth factor beta; green fluorescent protein; cytotoxicity; hodgkin disease; genetic transduction; transduction, genetic; t cell lymphoma; cytokine; cellular immunity; immunotherapy; mononuclear cell; cytotoxic t lymphocyte; t-lymphocytes, cytotoxic; gene therapy; long term care; transforming growth factor beta receptor; transforming growth factor beta1; receptors, transforming growth factor beta; tumor immunity; perforin; trans-activators; adjuvants, immunologic; cytokine release; epstein barr virus; herpesvirus 4, human; humans; human; priority journal; article
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