IMMU-13. Leveraging the immune milieu of experimental autoimmune encephalomyelitis to perpetuate an anti-tumor T cell response in glioblastoma

Abstract Glioblastoma (GBM) remains a paradigm of immunotherapy resistance, characterized by minimal effector T cell infiltration and failure to respond to immune checkpoint blockade (ICB) therapies such as anti-PD-1. In contrast, autoimmune states such as experimental autoimmune encephalomyelitis (EAE)—a murine model of multiple sclerosis—elicit robust, antigen-specific T cell responses within the central nervous system. We hypothesized that proinflammatory mechanisms sustaining autoimmunity in EAE could be co-opted to overcome immune tolerance in GBM. Single-cell RNA sequencing was used to profile T cell phenotypes from EAE and syngeneic GBM (CT-2A) models. EAE was induced in tumor-bearing mice, and tumor-specific EAE variants were generated using tumor cell lysate immunization. Cytokine expression was profiled via Luminex and white matter changes were visualized with diffusion tensor imaging and T2 mapping. Functional studies included adoptive transfer of CD3+ T cells or regulatory T cells, and hydrogel-based delivery of IL-6, IL-23, and anti-TGF-β to tumor-draining lymph nodes (TDLNs). T cell bioenergetics were assessed via Seahorse metabolic profiling and flow cytometry. EAE induction in GBM-bearing mice significantly improved survival and increased intratumoral Th1 and Th17 T cell infiltration. Tumor lysate immunization reproduced these effects and sensitized tumors to anti-PD-1 therapy. IL-6, IL-23, and IL-1β were identified as shared inflammatory mediators in both EAE and tumor-immunized states. Targeted lymphoid conditioning via hydrogels loaded with recombinant IL-6, IL-23, and anti-TGF-β reprogrammed TDLNs, enhanced T cell activation and oxidative phosphorylation, and extended survival (P<0.0001). Therefore, autoimmune inflammatory circuits can be repurposed to recondition the immunosuppressive GBM TME. Lymphoid niche modulation using a combination of IL-6, IL-23, and TGF-β blockade offers a novel strategy to sensitize GBM to currently available immunotherapeutic strategies such as anti-PD-1.