CD11c+ microglia promote dysfunctional T cell activation in diffuse midline glioma

Keane, L.; Baleviciute, A.; Cuesta-Marti, C.; Hincks, J.; McCarthy Hogan, M.; Sharvin, B. L.; McDermott, M.; O'Reilly, J.; Tofani, G. S. S.; du Chatinier, A.; Moloney, G. M.; Fitzgerald, P.; Foley, C.; O'Leary, O. F.; Phoenix, T. N.; Hullerman, E.; Larson, J. D.; Baker, S. J.; Clarke, G.; Cryan, J. F.

doi:10.64898/2026.09.18.752751

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bioRxiv · 10.64898/2026.09.18.752751

CD11c+ microglia promote dysfunctional T cell activation in diffuse midline glioma

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Abstract

Paediatric diffuse midline glioma (DMG) remains refractory to immunotherapy despite T-cell infiltration, indicating that local mechanisms actively suppress anti-tumour immunity. Using complementary genetic and orthotopic mouse models, we performed lineage-resolved profiling of the DMG immune microenvironment, resolving myeloid ontogeny and microglial states by distinguishing resident microglia from infiltrating bone marrow-derived macrophages. We identified microglia as the predominant tumour-associated myeloid population and discovered selective expansion of CD11c positive; microglia exhibiting enriched antigen-presentation and immune-regulatory transcriptional programs. Tumour-infiltrating CD4+; and CD8+; T cells exhibited chronic activation and exhaustion, while ligand receptor analysis predicted inhibitory microglia T cell communication. Pharmacological CSF1R inhibition depleted CD11c positive; microglia, attenuated antigen-presentation and immune-regulatory programs, and shifted tumour-infiltrating T cells toward a less exhausted phenotype. Together, these findings identify a previously unrecognised CD11 positive; microglia T-cell axis that establishes immune dysfunction in DMG and provide a rationale for combining myeloid- and T cell-targeted immunotherapies.

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Keane, L., Baleviciute, A., Cuesta-Marti, C., Hincks, J., McCarthy Hogan, M., Sharvin, B. L., McDermott, M., O'Reilly, J., Tofani, G. S. S., du Chatinier, A., Moloney, G. M., Fitzgerald, P., Foley, C., O'Leary, O. F., Phoenix, T. N., Hullerman, E., Larson, J. D., Baker, S. J., Clarke, G., Cryan, J. F.. 2026-09-22. CD11c+ microglia promote dysfunctional T cell activation in diffuse midline glioma. https://doi.org/10.64898/2026.09.18.752751

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