Potentiating dendritic cells to target hypoxic environment of brain tumor (TUM4P.911)

Glioblastoma multiforme (GBM) is the most malignant type of brain tumor with a mean survival time of one year. The most difficult problem to treat tumors is their hypoxic microenvironment that changes the phenotypic characteristic of immune cells. In hypoxic conditions, HIF-1α, a transcription factor, accumulates and stimulates various genes that promote angiogenesis and tumor growth. We studied tumor-mediated adaptations to hypoxia in glioblastoma cells and showed an upregulation of HIF-1α and VEGF expression in a 2- and 3- dimensional culture model. We then confirmed that hypoxic environment increases HIF-1α expression in dendritic cells (DCs), but downregulates the expression of HLA-DR, CD86 and HLA-ABC and affects their antigen processing and presentation capability. First, we reversed the effect of cancer-driven hypoxia on DC functionality in vitro. Then by injecting DCs containing antisense HIF-1α plasmid into mice with GBM, in vivo imaging revealed fluorescently labeled DCs migrating away from the site of injection into the spleen and mediastinal lymph nodes by 54h p.i., indicating chemoattraction of DCs to areas of ongoing inflammation. Finally, these DCs were loaded with glioblastoma tumor antigens via a glycotargeting approach which lead to potentiation of DC functionality and antigen presentation under hypoxic conditions. This translational approach has applicability in eradicating tumors by DC-based vaccination or being adjunct to existing radio- and chemotherapy.