IMMU-46. ARTIFICIAL INTELLIGENCE-DIRECTED, GENE THERAPY-BASED TRANSDIFFERENTIATION OF GLIOBLASTOMA TO FUNCTIONAL DENDRITIC CELLS AS NOVEL CANCER IMMUNOTHERAPY

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Abstract BACKGROUND Despite recent advances in tumor immunotherapy in solid tumors, success in GBM remains elusive, likely due to its poor immunogenicity and CNS barriers limiting immune cell trafficking. Here we describe a novel approach of stimulating glioma-specific immunity by transdifferentiating GBM cells in situ to induced dendritic cells (iDCs). METHODS We applied NETZEN, an integrated deep-learning and gene network-based ranking computational platform and identified cell fate determinants (CFDs) to convert GBM cells to DCs. CFDs were delivered using a viral vector. Transdifferentiation was assessed by immunophenotyping and iDCs functionally validated by their ability to prime naive T cells. RESULTS A four CFDs subnetwork anchored by PU.1 was sufficient to transdifferentiate mouse GBM cells to CD45+MHCII+ cells with high co-stimulatory CD80 expression and to induce nearly 98% of GBM cells to express 100-fold higher levels of MHCI. Consistent with a new identity of antigen-presenting cells (APC), the induced immune cells are growth arrested, exhibit 3-fold higher phagocytic activity and upregulate the canonical antigen processing and presenting machineries by 10-40 folds, resulting in 40-fold greater efficiency at processing ovalbumin and presenting SIINFEKL on MHCI compared to native GBM cells. Importantly, SIINFEKL-loaded iAPCs are capable of activating naive OTII-CD4+ and OTI-CD8+ T cells, indicating that they are DC-like. In addition, iDCs efficiently present tumor cell-intrinsic antigens and elicit >20-fold higher activation and cytotoxicity in tumor-specific T cells compared to native GBM cells. Lastly, intratumoral GBM-DC transdifferentiation in a syngeneic orthotopic GBM model produces a robust memory T cell response in deep cervical draining lymph nodes compared to control animals. CONCLUSIONS Our results comfirm that GBM-derived iDCs acquire functions similar to native DCs, and thus, lay the foundation for a novel therapeutic approach in which poorly immunogenic tumors like GBM may be forced to generate their own immunity from within through cell fate transdifferentiation.