MIP-1alpha antagonizes the effect of a GM-CSF-enhanced subcutaneous vaccine in a mouse glioma model.
Subcutaneous vaccination using granulocyte-macrophage colony-stimulating factor (GM-CSF)-transduced glioma cells substantially prolongs survival in the mouse GL261 glioma model. To potentiate the efficacy of GM-CSF-based vaccination, syngeneic C57BL/6 mice bearing pre-implanted intracerebral GL261 gliomas were vaccinated twice subcutaneously with various combinations of glioma cells retrovirally engineered to release GM-CSF, interleukin (IL)-4 or macrophage inflammatory protein (MIP)-1alpha. More than 80% of the animals vaccinated with GM-CSF-secreting or GM-CSF- and IL-4-secreting cells were long-term survivors (> 120 days). Their survival was significantly prolonged compared with animals vaccinated with wild-type cells, which died after a median survival time of 30 days. The combination of IL-4 with GM-CSF did not provide a survival advantage over GM-CSF alone, regardless of whether the animals carried a small or large intracranial tumor load. Further, when the animals were vaccinated with a mixture of GM-CSF-, IL-4- and MIP-1alpha-secreting cells, the median survival was 37 days, and only 22% of the animals in this group were long-term survivors, similar to the vaccination effect of non-modified glioma cells. Thus, unexpectedly, the co-expression of MIP-1alpha, which was meant to attract T cells for stimulation by GM-CSF- and IL-4-stimulated dendritic cells, nullified the induction of an immune response against the GL261 glioma by a GM-CSF- and IL-4-expressing subcutaneous vaccine.
Herrlinger
Ulrich
U
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, Tübingen, Germany. ulrich.herrlinger@uni-tuebingen.de
Aulwurm
Steffen
S
Strik
Herwig
H
Weit
Simone
S
Naumann
Ulrike
U
Weller
Michael
M
D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D004357:Drug Synergism; D005822:Genetic Vectors; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D007279:Injections, Subcutaneous; D015847:Interleukin-4 / Q000008:administration & dosage; D019402:Macrophage Inflammatory Proteins / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D012190:Retroviridae / Q000235:genetics; D016019:Survival Analysis; D014161:Transduction, Genetic; D017211:Treatment Failure; D014611:Vaccination
D019496:Cancer Vaccines; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D015847:Interleukin-4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor