Engineering human tumor-specific cytotoxic T cells to function in a hypoxic environment

Mol Ther. 2008 Mar;16(3):599-606. doi: 10.1038/ Epub 2008 Jan 29.


Hypoxia occurs in many tumors and reduces the effectiveness of radio- and chemotherapy. Hypoxia also impedes immune responses to tumors, reducing T lymphocyte production of cytokines such as interleukin-2 (IL-2) and interferon gamma, as well as the survival and proliferation of these cells. We constructed a lentiviral vector encoding a bidirectional hypoxia-inducible responsive element (HRE) derived from human vascular endothelial growth factor, which drives the hIL-2 gene and a marker gene. We used a model of human B cell lymphoma to show that tumor-specific T cells modified with this vector upregulate hIL-2 expression when oxygen tension is low in vitro and in vivo. The consequence of this effect is to increase T-cell survival and proliferation whilst sustaining effector function, even in O(2) concentrations as low as 1%. The phenotype of the transduced cells is unchanged, as is their ability to migrate to tumor. HRE-IL-2-modified cytotoxic T lymphocytes (CTLs) produce faster and more complete tumor regression than parental CTLs and increase overall survival. Hypoxia-resistant T cells may thus be of value in the treatment of human tumors in which areas of hypoxia may otherwise account for resistance to this therapeutic strategy.

Publication types

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

MeSH terms

  • Apoptosis / genetics
  • Apoptosis / physiology
  • Cell Hypoxia
  • Cell Line, Tumor
  • Cell Proliferation
  • Chemotaxis / genetics
  • Chemotaxis / physiology
  • Enzyme-Linked Immunosorbent Assay
  • Genetic Engineering / methods*
  • Genetic Vectors
  • Humans
  • Immunohistochemistry
  • Interleukin-2 / genetics
  • Interleukin-2 / metabolism
  • Lentivirus / genetics
  • Luciferases / genetics
  • Luciferases / metabolism
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Neoplasms / physiopathology
  • Phenotype
  • Response Elements / genetics
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / metabolism*
  • T-Lymphocytes, Cytotoxic / physiology*
  • Transduction, Genetic
  • Transgenes / genetics
  • Vascular Endothelial Growth Factor A / genetics


  • Interleukin-2
  • Vascular Endothelial Growth Factor A
  • Luciferases