Abstract
Cell-based immunotherapy has shown encouraging results in solid cancers including glioblastoma (GBM). However, major limitations of cell-based immunotherapy in GBM include difficulty with isolation and generation of effective antigen-presenting or immune effector cells, inadequate migration of immune cells across the blood brain barrier, and the high cost of cell-based vaccines. One approach to overcome these barriers is to convert GBM cells directly into immune cells of interest. Transdifferentiation, the transformation of one differentiated cell type directly into another without an intermediate pluripotent stage, has shown early promise in regenerative medicine, but has had a limited role in cancer therapy, especially for solid tumors. This is in large part due to the laborious and time-consuming process of identifying experimentally master fate determinants of various cell types. To enable this novel application, we have developed and experimentally validated two tandem computational platforms, GeneRep and nSCORE. Applying this novel tool to large quantities of published datasets, we successfully predicted cell fate determinants of tens of different cell types with several having been validated in transdifferentiation experiments by others and us, such as the conversions of astrocytes to neuronal stem cells and of fibroblasts to macrophages, etc. Here, we describe the process of combining a core set of hematopoietic stem cell, myeloid, and macrophage or dendritic cell (DC) fate determinants as predicted by GeneRep-nSCORE to efficiently transdifferentiate GBM cells into functional macrophages or dendritic cells, respectively, while neutralizing their malignant phenotype. This novel transdifferentiation has the potential for transformative impacts in many areas including DC vaccine immunotherapy and cancer therapy in general, and pioneers the concept that solid tumor cells can be converted into another cell type, and not just any cell type, but one that potentially can elicit a therapeutic response against itself.