Engineering human tumor-specific cytotoxic T cells to function in a hypoxic environment.
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.
Kim
Hongsung
H
Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Methodist Hospital, Houston, Texas 77030, USA.
Peng
Guangyong
G
Hicks
John M
JM
Weiss
Heidi L
HL
Van Meir
Erwin G
EG
Brenner
Malcolm K
MK
Yotnda
Patricia
P
D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002633:Chemotaxis / Q000235:genetics / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D005818:Genetic Engineering / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D007150:Immunohistochemistry; D007376:Interleukin-2 / Q000235:genetics / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D020218:Response Elements / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D014161:Transduction, Genetic; D019076:Transgenes / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D007376:Interleukin-2; D042461:Vascular Endothelial Growth Factor A; D008156:Luciferases