Adapting a transforming growth factor beta-related tumor protection strategy to enhance antitumor immunity.
Transforming growth factor beta (TGF-beta), 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-beta by expressing a nonfunctional TGF-beta 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-beta. 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-beta produced by this tumor. CTLs were transduced with a retrovirus vector expressing the dominant-negative TGF-beta type II receptor HATGF-betaRII-Deltacyt. HATGF-betaRII-Deltacyt- but not green fluorescence protein (eGFP)-transduced CTLs was resistant to the antiproliferative and anticytotoxic effects of exogenous TGF-beta. Additionally, receptor-transduced cells continued to secrete cytokines in response to antigenic stimulation. TGF-beta receptor ligation results in phosphorylation of Smad2, and this pathway was disrupted in HATGF-betaRII-Deltacyt-transduced CTLs, confirming blockade of the signal transduction pathway. Long-term expression of TGF-betaRII-Deltacyt did not affect CTL function, phenotype, or growth characteristics. Tumor-specific CTLs expressing HATGF-betaRII-Deltacyt should have a selective functional and survival advantage over unmodified CTLs in the presence of TGF-beta-secreting tumors and may be of value in treatment of these diseases.
Bollard
Catherine M
CM
Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Rössig
Claudia
C
Calonge
M Julia
MJ
Huls
M Helen
MH
Wagner
Hans-Joachim
HJ
Massague
Joan
J
Brenner
Malcolm K
MK
Heslop
Helen E
HE
Rooney
Cliona M
CM
D000276:Adjuvants, Immunologic / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use; D004268:DNA-Binding Proteins / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods; D004854:Herpesvirus 4, Human; D006689:Hodgkin Disease / Q000276:immunology / Q000628:therapy* / Q000821:virology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*; D051899:Smad2 Protein; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014161:Transduction, Genetic; D016212:Transforming Growth Factor beta / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D004268:DNA-Binding Proteins; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II