Local therapy strategies still provide only limited success in the treatment of glioblastoma, the most frequent primary brain tumor in adults, indicating global involvement of the brain in this fatal disease. To study the impact of neuroinflammation distant of the primary tumor site on the clinical course of patients with glioblastoma, we performed translocator protein (TSPO)-PET in patients with newly diagnosed glioblastoma, glioma WHO 2 and healthy controls and compared signals of the non-lesion (i.e. contralateral) hemisphere. Back-translation in syngeneic glioblastoma mice was used to characterize PET alterations on a cellular level. Ultimately, multiplex gene expression analyses served to profile immune cells in remote brain. Our study revealed elevated TSPO-PET signals in contralateral hemispheres of patients with newly diagnosed glioblastoma compared to healthy controls. Contralateral TSPO was associated with persisting epilepsy and poor prognosis independent of the tumor phenotype. Back-translation pinpointed myeloid cells as the source of TSPO-PET signal increases and revealed a complex immune signature comprised of joint myeloid cell activation and immunosuppression in distant brain regions. In brief, neuroinflammation within the contralateral hemisphere is associated with poor outcome in patients with newly diagnosed glioblastoma. TSPO-PET serves to detect patients with global neuroinflammation who may benefit from immunomodulatory strategies.

NLA and MB are members of the Neuroimaging Committee of the EANM. JCT received research grants from Novocure and Munich Surgical Imaging and a speaker honorarium from Seagen. NLA received funding from Novocure. MB received speaker honoraria from Roche, GE healthcare and Life Molecular Imaging and is an advisor of Life Molecular Imaging. VCR received speaker honoraria from Novocure. All other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

This project was partly funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) (FOR 2858 project numbers 421887978 and 422188432 and Research Training Group GRK 2274). NLA is supported by a research grant of the Else Kroener-Fresenius-Stiftung. MB was funded by the Deutsche Forschungsgemeinschaft (DFG) under Germanys Excellence Strategy within the framework of the Munich Cluster for Systems Neurology (EXC 2145 SyNergy, ID 390857198). SVK was supported by the Verein zur Foerderung von Wissenschaft und Forschung an der Medizinischen Fakultaet der LMU Muenchen (WiFoMed) and the Friedrich-Baur-Stiftung. AH received funding by the Bavarian Cancer Research Center (BZKF) and is currently funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation, 545058105.

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The ethics committee of the Ludwig-Maximilians-University gave ethical approval for this work (approval number 17-457, approval numbers for data on healthy individuals 601-16, 17-569, 17-755)

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