MAPK-driven glioma progression and reprogramming of the tumor-associated immune response

BACKGROUND: In brain tumors, the immunosuppressive microenvironment leads to tumor aggressiveness and immunotherapy resistance. To identify factors that regulate the glioma immune landscape, we took advantage of the disease trajectory of the MAPK-driven glioma, pleomorphic xanthoastrocytoma (PXA), which evolves from an immune-rich low-grade tumor to an aggressive glioma. METHODS: Using a multiomics approach that included single-nucleus RNA sequencing (snRNA-seq), spatial transcriptomics, and spatial proteomics, a cohort of 38 tumors, including 10 longitudinal pairs, was profiled. RESULTS: Tumor progression was associated with transition to a more proliferative progenitor state and increased hypoxia. Hypoxic reprogramming of the immune landscape included increased TGF-β signaling and altered chemokine signaling, including decreased CXCL14 and CXCL16-CXCR6 signaling important in immune cell recruitment and activation. The resulting immune landscape was spatially reorganized with reduced HLA Class II expression, reduced CD8+ and CD4⁺ T cells, and dominated by immunosuppressive myeloid cells. CONCLUSIONS: Hypoxia and chemokine signaling emerged as key components of the glioma-immune landscape that evolve with tumor progression. These findings identify potential therapeutic opportunities in PXA, and they argue that optimal immunomodulatory strategies in glioma will differ along the disease trajectory.