Regression of AK7 malignant mesothelioma established in immunocompetent mice following intratumoral gene transfer of interferon gamma

Cancer Gene Ther. 2003 Jun;10(6):481-90. doi: 10.1038/sj.cgt.7700594.


Malignant mesothelioma (MM) is a lethal tumor linked with a prior exposure to asbestos in which limited progress has been made so far using conventional therapies. MM is an example of a "nonimmunogenic" tumor characterized by a fibrous stroma and an absence of infiltrating T lymphocytes. High levels of transforming growth factor-beta (TGF-beta) produced by mesothelioma cells have been related to the immune tolerance towards the tumor. In order to evaluate the effect of local delivery of cytokines such as interferon gamma (IFN-gamma) by gene transfer, we characterized and used a murine model, AK7, which appeared very similar to human mesothelioma. AK7 cells expressed low levels of major histocompatibility class I and class II antigens and secreted high levels of latent TGF-beta. The TGF-beta pathway in AK7 cells is operative but inefficient because endogenous TGF-beta is predominantly inactive. Treatment of pre-established AK7 tumors by direct intratumoral injection of an adenovirus vector expressing murine IFN-gamma, Ad.mIFN-gamma, led to significant tumor regression. Peripheral tumor infiltration by CD4+ and CD8+ T lymphocytes in the treated tumors appeared to be because of the induction of an immune response. Tumor relapse was observed, which could be due to local TGF-beta secretion by remaining tumor cells.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Apoptosis
  • Blotting, Western
  • Caspase 3
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Separation
  • Cytokines / metabolism
  • DNA, Complementary / metabolism
  • Down-Regulation
  • Female
  • Flow Cytometry
  • Gene Transfer Techniques*
  • Genetic Therapy / methods*
  • Immunohistochemistry
  • Interferon-gamma / genetics*
  • Interferon-gamma / metabolism
  • Mesothelioma / metabolism
  • Mesothelioma / pathology
  • Mesothelioma / therapy*
  • Mice
  • Mice, Inbred C57BL
  • Neoplasm Transplantation
  • Phosphorylation
  • Polymerase Chain Reaction
  • RNA / metabolism
  • T-Lymphocytes / metabolism
  • Time Factors
  • Transforming Growth Factor beta / metabolism
  • Up-Regulation


  • Cytokines
  • DNA, Complementary
  • Transforming Growth Factor beta
  • RNA
  • Interferon-gamma
  • CASP3 protein, human
  • Casp3 protein, mouse
  • Caspase 3
  • Caspases