Dynamics of Microglia-Glioblastoma Crosstalk at the Far Infiltration Zone

The interaction of glioblastoma (GB) and microglia is critical due to its implications for tumor progression, immune response modulation, and potential therapeutic strategies. However, the role of microglia in GB pathogenesis remains unclear, especially regarding the in vivo dynamics of their interplay. Performing three-photon imaging in an autochthonous, immunocompetent mouse GB model, we examined tumor/microglia dynamics within previously inaccessible regions at the GB far infiltration zone in the corpus callosum. Initially, microglia increased tissue surveillance upon encountering GB-cells in sparsely infiltrated areas. In contrast, when GB-cell density increased, microglia reduced surveillance, suggesting a biphasic response to tumor invasion. Additionally, microglia were not uniformly attracted to infiltrating GB-cells; only a subset moved directionally toward them within a defined spatial range. This study provides insight into the heterogeneity of the immune response to tumor invasion and the dynamics of microglia-GB interactions in vivo.

Note:
Funding Information: This work was supported by the DZNE, and grants to MF and PS by the European Union ERC-CoG (MicroSynCom 865618, H3.3Cancer 616744). MF received funding from the German research foundation DFG (SFB1089 C01, B06; SPP2395) and is a member of the DFG excellence cluster ImmunoSensation2.

Declaration of Interests: UH received advisory board and speakers honoraria from Medac and Bayer and advisory board honoraria from Servier and OncomagnetX. All other authors declare no competing interests.

Ethical Approval Statement: All experiments were performed according to animal care guidelines and approved by the Landesamt für Natur, Umwelt und Verbraucherschutz of North Rhine-Westphalia (Germany) (#81-02.04.2018.A148). The GLORIA trial (SNOXA12C401, 2018-004064-62, NCT04121455) was first registered on EudraCT upon approval by the German authority (Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM)) in May 2019 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-004064-62/DE). Further qualitative and quantitative analysis of tissue sections were also granted by the local ethics committee as of July 2023 (222/23-EP).

Keywords: Glioblastoma, Microglia, Three-photon microscopy, Autochthonous mouse model, Corpus callosum, Diffuse infiltration, Migration, Motility

Suggested Citation: Suggested Citation

Nebeling, Felix C. and Fuhrmann, Falko and Mittag, Manuel and Mussachio, Fabrizio and Gockel, Nala and Friker, Lea L. and Leonardelli, Sonia and Filser, Severin and Deli, A and Stork, Miriam and Bano, Daniele and Pietsch, Torsten and Parrinello, Simona and Hölzel, Michael and Herrlinger, Ulrich and Salomoni, Paolo and Fuhrmann, Martin and Administrator, Sneak Peek, Dynamics of Microglia-Glioblastoma Crosstalk at the Far Infiltration Zone. Available at SSRN: https://ssrn.com/abstract=4997252 or http://dx.doi.org/10.2139/ssrn.4997252

This version of the paper has not been formally peer reviewed.