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

Catherine M. Bollard, Claudia Rössig, M. Julia Calonge, M. Helen Huls, Hans Joachim Wagner, Joan Massague, Malcolm K. Brenner, Helen E. Heslop, Cliona M. Rooney

Research output: Contribution to journalArticle

234 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)3179-3187
Number of pages9
JournalBlood
Volume99
Issue number9
DOIs
StatePublished - May 1 2002

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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