Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Fermi, V.; Warta, R.; Rapp, C.; Knoll, M.; Jungwirth, G.; Jungk, C.; Dao Trong, P.; von Deimling, A.; Abdollahi, A.; Unterberg, A.; Herold-Mende, C.

doi:10.1101/2022.10.20.511747

bioRxiv · 10.1101/2022.10.20.511747

Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition

Fermi, V.·Warta, R.·Rapp, C.·Knoll, M.·Jungwirth, G.·Jungk, C.·Dao Trong, P.·von Deimling, A.·Abdollahi, A.·Unterberg, A.·Herold-Mende, C.

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Abstract

Targeting immunosuppressive and protumorigenic glioblastoma-associated macrophages and microglial cells (GAMs) holds great potential to improve patient outcomes. Although CSF1R has emerged as a promising target to reprogram anti-inflammatory M2-like GAMs, relevant treatment data on human, tumor-educated GAMs and innovative patient-derived 3D tumor organoid models to study the influence on adaptive immunity and the effectiveness of treatment in a complex and entirely autologous setting are largely lacking. We performed a comprehensive phenotypical, transcriptional and functional analysis of primary, patient-derived GAMs upon treatment with the CSF1R-targeting drugs PLX3397, BLZ945, and GW2580. The most effective reprogramming of GAMs was observed upon GW2580 treatment, which led to a downregulation of M2-related markers and signaling pathways, while M1-like markers, phagocytosis, and T-cell killing were substantially increased. Moreover, treatment of patient-derived glioblastoma organoids with GW2580 confirmed successful reprogramming together with reduced tumor cell proliferation, indicating that treatment with GW2580 could be an important pillar in the future therapy of GBM.

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Fermi, V., Warta, R., Rapp, C., Knoll, M., Jungwirth, G., Jungk, C., Dao Trong, P., von Deimling, A., Abdollahi, A., Unterberg, A., Herold-Mende, C.. 2022-10-21. Reprogramming M2-polarized patient-derived glioblastoma associated microglia/macrophages via CSF1R inhibition. https://doi.org/10.1101/2022.10.20.511747

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