Myeloid-derived immunosuppression of chimeric antigen receptor T cells in the neuronal microenvironment of glioblastoma - PubMed
3 hours ago
- #Glioblastoma
- #CAR-T cells
- #Immunosuppression
- CAR-T cell therapy is largely ineffective in glioblastoma (GB) due to the immunosuppressive microenvironment and tumor heterogeneity.
- A human neocortical brain slice model was used to study interactions between NKG2D CAR-T cells and the tumor ecosystem using PIC-seq, spatial transcriptomics, and gene regulatory network reconstruction.
- CAR-T cells showed early tumor-suppressive effects but were not sustained in the slice model.
- Single-cell profiling revealed CAR CD8 T cells adopt an effector-skewed activation state with upregulated checkpoint receptors and exhaustion-associated transcription factors.
- Tumor-associated macrophages displayed enhanced phagocytic programs and co-localized with mesenchymal-like GB cells in hypoxic regions.
- Gene regulatory network analysis identified MAF and BACH2 as regulators of CD8 T cell state, with MAF linked to exhaustion-like features and BACH2 to less differentiated programs.
- In silico perturbation analyses suggested a reciprocal effect of MAF and BACH2 on CD8 T cell transcriptional trajectories.
- The study maps microenvironmental and transcriptional changes linked to CAR-T cell dysfunction in GB, identifying pathways for more durable therapies.