Antitumor activity of EBV-specific T lymphocytes transduced with a dominant negative TGF-beta receptor

J Immunother. 2008 Jun;31(5):500-5. doi: 10.1097/CJI.0b013e318177092b.


Transforming growth factor (TGF)-beta is produced in most human tumors and markedly inhibits tumor antigen-specific cellular immunity, representing a major obstacle to the success of tumor immunotherapy. TGF-beta is produced in Epstein-Barr virus (EBV)-positive Hodgkin disease and non-Hodgkin lymphoma both by the tumor cells and by infiltrating T-regulatory cells and may contribute the escape of these tumors from infused EBV-specific T cells. To determine whether tumor antigen-specific cytotoxic T lymphocytes (CTLs) can be shielded from the inhibitory effects of tumor-derived TGF-beta, we previously used a hemagglutinin-tagged dominant negative TGF-betaRII expressed from a retrovirus vector to provide CTLs with resistance to the inhibitory effects of TGF-beta in vitro. We now show that human tumor antigen-specific CTLs can be engineered to resist the inhibitory effects of tumor-derived TGF-beta both in vitro and in vivo using a clinical grade retrovirus vector in which the dominant negative TGF-beta type II receptor (DNRII) was modified to remove the immunogenic hemagglutinin tag. TGF-beta-resistant CTL had a functional advantage over unmodified CTL in the presence of TGF-beta-secreting EBV-positive lymphoma, and had enhanced antitumor activity, supporting the potential value of this countermeasure.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Genes, Dominant
  • Herpesvirus 4, Human / immunology*
  • Humans
  • Mice
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / metabolism*
  • Neoplasms / pathology*
  • Receptors, Transforming Growth Factor beta / genetics*
  • Receptors, Transforming Growth Factor beta / metabolism*
  • T-Lymphocytes / cytology
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Transforming Growth Factor beta / metabolism
  • Transforming Growth Factor beta / pharmacology
  • Xenograft Model Antitumor Assays


  • Receptors, Transforming Growth Factor beta
  • Transforming Growth Factor beta