Interrogating Glioma-Associated Microglia and Macrophage Dynamics Under CSF-1R Therapy with Multitracer In Vivo PET/MRI

Foray, Claudia; Barca, Cristina; Winkeler, Alexandra; Wagner, Stefan; Hermann, Sven; Schaefers, Michael; Grauer, Oliver; Zinnhardt, Bastian

doi:10.2967/jnumed.121.263318

Cited by 12 publications

(12 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…TSPO is not only expressed in myeloid cells of the tumor microenvironment (TME) but also in tumor cells in dependence of the glioma grade ( 1 ). Despite the expression by various cell types, TSPO could serve as a potential imaging biomarker to characterize the immunosuppressive phenotype of glioblastoma during immunomodulatory treatment ( 2 ). Furthermore, due to the assumed strong elevation of TSPO in the infiltration zone ( 1 ), this biomarker may have potential to identify brain regions that are subject to tumor recurrence.…”

Section: Introductionmentioning

confidence: 99%

“…The value of TSPO imaging in glioma was already determined in prognostication and detection of tumor heterogeneity ( 5 , 6 ). For back translation and mechanistic elucidation of observations in humans as well as for TSPO biomarker monitoring during experimental testing of therapeutics, animal models provide a tremendous value across brain diseases ( 2 , 7 , 8 ). First experimental glioblastoma investigations with murine GL261 in immunocompetent mice ( 9 ), human P3 in immunodeficient mice ( 10 ), and human U87 in immunodeficient rats ( 11 ) indicated feasibility of TSPO PET monitoring by different radiotracers.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

Bartos

Kirchleitner²,

Blobner³

et al. 2022

Front. Med.

View full text Add to dashboard Cite

IntroductionThe 18 kDa translocator protein (TSPO) receives growing interest as a biomarker in glioblastoma. Mouse models can serve as an important tool for the investigation of biomarkers in glioblastoma, but several glioblastoma models indicated only low TSPO-PET signals in contrast to high TSPO-PET signals of human glioblastoma. Thus, we aimed to investigate TSPO-PET imaging in the syngeneic immunocompetent SB28 mouse model, which is thought to closely represent the tumor microenvironment (TME) of human glioblastoma.MethodsDynamic TSPO-PET/CT imaging was performed for 60 min after injection of 13.6 ± 4.2 MBq [18F]GE-180. Contrast enhanced CT (ceCT) was acquired prior to PET and served for assessment of tumor volumes and attenuation correction. SB28 and sham mice were imaged at an early (week-1; n = 6 SB28, n = 6 sham) and a late time-point (week-3; n = 8 SB28, n = 9 sham) after inoculation. Standard of truth ex vivo tumor volumes were obtained for SB28 mice at the late time-point. Tracer kinetics were analyzed for the lesion site and the carotid arteries to establish an image derived input function (IDIF). TSPO-PET and ceCT lesion volumes were compared with ex vivo volumes by calculation of root-mean-square-errors (RMSE). Volumes of distribution (VTmax/mean) in the lesion were calculated using carotid IDIF and standardized uptake values (SUVmax/mean) were obtained for a 40–60 min time frame.ResultsHigher uptake rate constants (K1) were observed for week-1 SB28 tumor lesions when compared to week-3 SB28 tumor lesions. Highest agreement between TSPO-PET lesion volumes and ex vivo tumor volumes was achieved with a 50% maximum threshold (RMSE-VT: 39.7%; RMSE-SUV: 34.4%), similar to the agreement of ceCT tumor volumes (RMSE: 30.1%). Lesions of SB28 mice had higher PET signal when compared to sham mice at week-1 (VTmax 6.6 ± 2.9 vs. 3.9 ± 0.8, p = 0.035; SUVmax 2.3 ± 0.5 vs. 1.2 ± 0.1, p < 0.001) and PET signals remained at a similar level at week-3 (VTmax 5.0 ± 1.6 vs. 2.7 ± 0.8, p = 0.029; SUVmax 1.9 ± 0.5 vs. 1.2 ± 0.2, p = 0.0012). VTmax correlated with SUVmax (R2 = 0.532, p < 0.001).ConclusionTSPO-PET imaging of immunocompetent SB28 mice facilitates early detection of tumor signals over sham lesions. SB28 tumors mirror high TSPO-PET signals of human glioblastoma and could serve as a valuable translational model to study TSPO as an imaging biomarker.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

Bartos

Kirchleitner²,

Blobner³

et al. 2022

Front. Med.

View full text Add to dashboard Cite

show abstract

“…In our study, the inhibition of activated microglia reduced pathological angiogenesis in the early stage and then rescued the over-apoptosis of photoreceptors. Moreover, the therapy of PLX5622-mediated modulation of GAMM might be a novel therapy against glioma [ 50 ]. Therefore, local inhibition of microglia activation has considerable therapeutic prospects in ocular diseases.…”

Section: Discussionmentioning

confidence: 99%

Distinguished Functions of Microglia in the Two Stages of Oxygen-Induced Retinopathy: A Novel Target in the Treatment of Ischemic Retinopathy

Zhou

Jing

Niu

et al. 2022

Life

View full text Add to dashboard Cite

Microglia is the resident immune cell in the retina, playing the role of immune surveillance in a traditional concept. With the heated focus on the mechanisms of microglia in pathological conditions, more and more functions of microglia have been discovered. Although the regulating role of microglia has been explored in ischemic retinopathy, little is known about its mechanisms in the different stages of the pathological process. Here, we removed microglia in the oxygen-induced retinopathy model by PLX5622 and revealed that the removal of activated microglia reduced pathological angiogenesis in the early stage after ischemic insult and alleviated the over-apoptosis of photoreceptors in the vessel remodeling phase. Our results indicated that microglia might play distinguished functions in the angiogenic and remodeling stages, and that the inhibition of microglia might be a promising target in the future treatment of ischemic retinopathy.

show abstract

“…The second-and third-generation tracers have shown superior imaging properties, while they are not yet fully characterized [34]. The use of TSPO PET tracers has been corroborated in several glioma models and showed to (i) improve tumor and immune cell detection, (ii) provide complementary information to [ 18 F]FET PET and MR imaging, (iii) be a suitable biomarker for glioma growth and immune cell infiltration, and (iv) define glioma heterogeneity in combination with other imaging modalities [33,[35][36][37][38][39]. In patients with positive uptake for both tracers, the mean percentage of overlap was 24.56%.…”

Section: Translocator Protein (Tspo) Pet Imagingmentioning

confidence: 99%

“…The authors observed that [ 18 F]DPA-714 PET VOI was not significantly changed with GAMs depletion while the progression of glioma-associated inflammation was slowed down following inhibitor withdrawal. Subsequently, Foray et al employed a colony-stimulating factor 1 receptor (CSF-1R) inhibitor to efficiently deplete GAMs within the TME in an orthotopic syngeneic GL261 mouse model and assessed therapy response using [ 18 F]FET and [ 18 F]DPA-714 PET imaging at days 7, 14 and 21 post-injection (Figure 4) [37]. The authors observed that [ 18 F]DPA-714 PET VOI was not significantly changed with GAMs depletion while the progression of glioma-associated inflammation was slowed down following inhibitor withdrawal.…”

Section: Therapy Readoutmentioning

confidence: 99%

In Vivo Quantitative Imaging of Glioma Heterogeneity Employing Positron Emission Tomography

Barca

Foray

Zinnhardt

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Glioblastoma is the most common primary brain tumor, highly aggressive by being proliferative, neovascularized and invasive, heavily infiltrated by immunosuppressive glioma-associated myeloid cells (GAMs), including glioma-associated microglia/macrophages (GAMM) and myeloid-derived suppressor cells (MDSCs). Quantifying GAMs by molecular imaging could support patient selection for GAMs-targeting immunotherapy, drug target engagement and further assessment of clinical response. Magnetic resonance imaging (MRI) and amino acid positron emission tomography (PET) are clinically established imaging methods informing on tumor size, localization and secondary phenomena but remain quite limited in defining tumor heterogeneity, a key feature of glioma resistance mechanisms. The combination of different imaging modalities improved the in vivo characterization of the tumor mass by defining functionally distinct tissues probably linked to tumor regression, progression and infiltration. In-depth image validation on tracer specificity, biological function and quantification is critical for clinical decision making. The current review provides a comprehensive overview of the relevant experimental and clinical data concerning the spatiotemporal relationship between tumor cells and GAMs using PET imaging, with a special interest in the combination of amino acid and translocator protein (TSPO) PET imaging to define heterogeneity and as therapy readouts.

show abstract

Interrogating Glioma-Associated Microglia and Macrophage Dynamics Under CSF-1R Therapy with Multitracer In Vivo PET/MRI

Abstract: Visual Abstract

Cited by 12 publications

References 29 publications

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

18 kDa translocator protein positron emission tomography facilitates early and robust tumor detection in the immunocompetent SB28 glioblastoma mouse model

Distinguished Functions of Microglia in the Two Stages of Oxygen-Induced Retinopathy: A Novel Target in the Treatment of Ischemic Retinopathy

In Vivo Quantitative Imaging of Glioma Heterogeneity Employing Positron Emission Tomography

Contact Info

Product

Resources

About