Adapting a transforming growth factor –related tumor protection strategy to enhance antitumor immunity

Transforming growth factor (TGF), 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 TGFby expressing a nonfunctional TGFreceptor. 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. 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 TGFproduced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGFtype II receptor HATGFRIIcyt. HATGFRIIcyt– but not green fluorescence protein (eGFP)– transduced CTLs was resistant to the antiproliferative and anticytotoxic effects of exogenous TGF. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGFreceptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGFRIIcyt– transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGFRIIcyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGFRIIcyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF–secreting tumors and may be of value in treatment of these diseases. (Blood. 2002;99:3179-3187)