Increased TSPO PET signal after radiochemotherapy in IDH-wildtype glioma—indicator for treatment-induced immune activation?

Quach, Stefanie; Holzgreve, Adrien; Baumgarten, Louisa von; Niyazi, Maximilian; Thon, Niklas; Stöcklein, Sophia; Bartenstein, Peter; Tonn, Jörg‐Christian; Albert, Nathalie L.

doi:10.1007/s00259-022-05844-3

Cited by 8 publications

(5 citation statements)

References 12 publications

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“…with [ 18 F]FET PET, might capture the treatment-induced immune response as a potential biomarker (25). In addition, some promising preclinical studies hint at the potential future clinical value of multitracer approaches for PET imaging of glioma.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH–Wild-Type Glioblastoma

et al. 2023

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The 18-kDa translocator protein (TSPO) is gaining recognition as a relevant target in glioblastoma imaging. However, data on the potential prognostic value of TSPO PET imaging in glioblastoma are lacking. Therefore, we investigated the association of TSPO PET imaging results with survival outcome in a homogeneous cohort of glioblastoma patients. Methods: Patients were included who had newly diagnosed, histologically confirmed isocitrate dehydrogenase (IDH)-wild-type glioblastoma with available TSPO PET before either normofractionated radiotherapy combined with temozolomide or hypofractionated radiotherapy. SUV max on TSPO PET, TSPO binding affinity status, tumor volumes on MRI, and further clinical data, such as O 6 -alkylguanine DNA methyltransferase (MGMT) and telomerase reverse transcriptase (TERT) gene promoter mutation status, were correlated with patient survival. Results: Forty-five patients (median age, 63.3 y) were included. Median SUV max was 2.2 (range, 1.0-4.7). A TSPO PET signal was associated with survival: High uptake intensity (SUV max . 2.2) was related to significantly shorter overall survival (OS; 8.3 vs. 17.8 mo, P 5 0.037). Besides SUV max , prognostic factors for OS were age (P 5 0.046), MGMT promoter methylation status (P 5 0.032), and T2-weighted MRI volume (P 5 0.031). In the multivariate survival analysis, SUV max in TSPO PET remained an independent prognostic factor for OS (P 5 0.023), with a hazard ratio of 2.212 (95% CI, for death in cases with a high TSPO PET signal (SUV max . 2.2). Conclusion: A high TSPO PET signal before radiotherapy is associated with significantly shorter survival in patients with newly diagnosed IDH-wild-type glioblastoma. TSPO PET seems to add prognostic insights beyond established clinical parameters and might serve as an informative tool as clinicians make survival predictions for patients with glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH–Wild-Type Glioblastoma

et al. 2023

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“…TSPO is frequently overexpressed in glioma [ 3 , 14 , 71 , 79 ], and a possible connection between TSPO enrichment and high malignancy has been suggested. TSPO is intensely discussed as an imaging target for prognosis [ 14 , 58 ], during therapy [ 22 , 57 , 62 , 63 ], and in CNS pathologies with neuroinflammatory components [ 4 , 18 , 29 , 78 ]. Nevertheless, systematic approaches to link TSPO imaging to its histopathological correlates that would add informational content on TSPO as a biomarker are largely missing.…”

Section: Discussionmentioning

confidence: 99%

“…TSPO-PET imaging is a potential prognostic marker in patients suffering from diffuse gliomas [ 14 , 58 ]. It has been described to mark the tumor microenvironment (TME) with its myeloid compartment and to indicate therapy-induced changes during tumor progression [ 22 , 57 , 79 ]. Regarding the cellular source of TSPO-PET, tumor cells, reactive astrocytes, endothelial cells, and macrophages/ microglia have been discussed [ 33 , 53 , 60 , 79 ].…”

Section: Introductionmentioning

confidence: 99%

Translocator protein (18kDA) (TSPO) marks mesenchymal glioblastoma cell populations characterized by elevated numbers of tumor-associated macrophages

Weidner,

Lorenz,

Quach

et al. 2023

acta neuropathol commun

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TSPO is a promising novel tracer target for positron-emission tomography (PET) imaging of brain tumors. However, due to the heterogeneity of cell populations that contribute to the TSPO-PET signal, imaging interpretation may be challenging. We therefore evaluated TSPO enrichment/expression in connection with its underlying histopathological and molecular features in gliomas. We analyzed TSPO expression and its regulatory mechanisms in large in silico datasets and by performing direct bisulfite sequencing of the TSPO promotor. In glioblastoma tissue samples of our TSPO-PET imaging study cohort, we dissected the association of TSPO tracer enrichment and protein labeling with the expression of cell lineage markers by immunohistochemistry and fluorescence multiplex stains. Furthermore, we identified relevant TSPO-associated signaling pathways by RNA sequencing.We found that TSPO expression is associated with prognostically unfavorable glioma phenotypes and that TSPO promotor hypermethylation is linked to IDH mutation. Careful histological analysis revealed that TSPO immunohistochemistry correlates with the TSPO-PET signal and that TSPO is expressed by diverse cell populations. While tumor core areas are the major contributor to the overall TSPO signal, TSPO signals in the tumor rim are mainly driven by CD68-positive microglia/macrophages. Molecularly, high TSPO expression marks prognostically unfavorable glioblastoma cell subpopulations characterized by an enrichment of mesenchymal gene sets and higher amounts of tumor-associated macrophages.In conclusion, our study improves the understanding of TSPO as an imaging marker in gliomas by unveiling IDH-dependent differences in TSPO expression/regulation, regional heterogeneity of the TSPO PET signal and functional implications of TSPO in terms of tumor immune cell interactions.

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“…Unlike in a human study, where tissue sampling is ethically warranted in case of newly diagnosed tumors and suspected recurrence only, an analogous animal study could include tissue sampling during and after therapy. This would be especially useful to determine how TSPO expression and its cellular distribution changes during treatment as well as early and later after treatment, and if an increase at different timepoints has to be interpreted differently, such as in the context of an inflammatory reaction to treatment [52,53]. These aspects will be covered in upcoming studies.…”

Section: Discussionmentioning

confidence: 99%

TSPO PET signal using [18F]GE180 is associated with survival in recurrent gliomas

Quach

Holzgreve

Kaiser

et al. 2022

Eur J Nucl Med Mol Imaging

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Purpose Glioma patients, especially recurrent glioma, suffer from a poor prognosis. While advances to classify glioma on a molecular level improved prognostication at initial diagnosis, markers to prognosticate survival in the recurrent situation are still needed. As 18 kDa translocator protein (TSPO) was previously reported to be associated with aggressive histopathological glioma features, we correlated the TSPO positron emission tomography (PET) signal using [18F]GE180 in a large cohort of recurrent glioma patients with their clinical outcome. Methods In patients with [18F]GE180 PET at glioma recurrence, [18F]GE180 PET parameters (e.g., SUVmax) as well as other imaging features (e.g., MRI volume, [18F]FET PET parameters when available) were evaluated together with patient characteristics (age, sex, Karnofsky-Performance score) and neuropathological features (e.g. WHO 2021 grade, IDH-mutation status). Uni- and multivariate Cox regression and Kaplan–Meier survival analyses were performed to identify prognostic factors for post-recurrence survival (PRS) and time to treatment failure (TTF). Results Eighty-eight consecutive patients were evaluated. TSPO tracer uptake correlated with tumor grade at recurrence (p < 0.05), with no significant differences in IDH-wild-type versus IDH-mutant tumors. Within the subgroup of IDH-mutant glioma (n = 46), patients with low SUVmax (median split, ≤ 1.60) had a significantly longer PRS (median 41.6 vs. 25.3 months, p = 0.031) and TTF (32.2 vs 8.7 months, p = 0.001). Also among IDH-wild-type glioblastoma (n = 42), patients with low SUVmax (≤ 1.89) had a significantly longer PRS (median not reached vs 8.2 months, p = 0.002). SUVmax remained an independent prognostic factor for PRS in the multivariate analysis including CNS WHO 2021 grade, IDH status, and age. Tumor volume defined by [18F]FET PET or contrast-enhanced MRI correlated weakly with TSPO tracer uptake. Treatment regimen did not differ among the median split subgroups. Conclusion Our data suggest that TSPO PET using [18F]GE180 can help to prognosticate recurrent glioma patients even among homogeneous molecular subgroups and may therefore serve as valuable non-invasive biomarker for individualized patient management. Graphical abstract

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Increased TSPO PET signal after radiochemotherapy in IDH-wildtype glioma—indicator for treatment-induced immune activation?

Cited by 8 publications

References 12 publications

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH–Wild-Type Glioblastoma

Prognostic Value of TSPO PET Before Radiotherapy in Newly Diagnosed IDH–Wild-Type Glioblastoma

Translocator protein (18kDA) (TSPO) marks mesenchymal glioblastoma cell populations characterized by elevated numbers of tumor-associated macrophages

TSPO PET signal using [18F]GE180 is associated with survival in recurrent gliomas

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