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

Abstract 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, 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 CXC-chemokine ligand 14 (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.