TY - JOUR
T1 - Adapting a transforming growth factor β-related tumor protection strategy to enhance antitumor immunity
AU - Bollard, Catherine M.
AU - Rössig, Claudia
AU - Julia Calonge, M.
AU - Helen Huls, M.
AU - Wagner, Hans Joachim
AU - Massague, Joan
AU - Brenner, Malcolm K.
AU - Heslop, Helen E.
AU - Rooney, Cliona M.
PY - 2002/5/1
Y1 - 2002/5/1
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.V99.9.3179
DO - 10.1182/blood.V99.9.3179
M3 - Article
C2 - 11964281
AN - SCOPUS:0036566184
VL - 99
SP - 3179
EP - 3187
JO - Blood
JF - Blood
SN - 0006-4971
IS - 9
ER -