Abstract
BackgroundMany malignant tumours have increased TSPO expression, which has been related to a poor prognosis. TSPO-PET tracers have not comprehensively been evaluated in peripherally located tumours. This study aimed to evaluate whether N,N-diethyl-2-(2-(4-([18F]fluoro)phenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl)acetamide ([18F]F-DPA) can reflect radiotherapy (RT)-induced changes in TSPO activity in head and neck squamous cell carcinoma (HNSCC).MethodsRT was used to induce inflammatory responses in HNSCC xenografts and cells. [18F]F-DPA uptake was measured in vivo in non-irradiated and irradiated tumours, followed by ex vivo biodistribution, autoradiography, and radiometabolite analysis. In vitro studies were performed in parental and TSPO-silenced (TSPO siRNA) cells. TSPO protein and mRNA expression, as well as tumour-associated macrophages (TAMs), were also assessed.ResultsIn vivo imaging and ex vivo measurement revealed significantly higher [18F]F-DPA uptake in irradiated, compared to non-irradiated tumours. In vitro labelling studies with cells confirmed this finding, whereas no effect of RT on [18F]F-DPA uptake was detected in TSPO siRNA cells. Radiometabolite analysis showed that the amount of unchanged [18F]F-DPA in tumours was 95%, also after irradiation. PK11195 pre-treatment reduced the tumour-to-blood ratio of [18F]F-DPA by 73% in xenografts and by 88% in cells. TSPO protein and mRNA levels increased after RT, but were highly variable. The proportion of M1/M2 TAMs decreased after RT, whereas the proportion of monocytes and migratory monocytes/macrophages increased.Conclusions[18F]F-DPA can detect changes in TSPO expression levels after RT in HNSCC, which does not seem to reflect inflammation. Further studies are however needed to clarify the physiological mechanisms regulated by TSPO after RT.
Highlights
Translocator protein (TSPO)-targeting positron emission tomography (PET) imaging is currently mainly used for imaging neurodegenerative diseases [1] and brain gliomas [2] as TSPO is considered a biomarker of neuroinflammation and microglial activation
Several studies [5, 6, 8] have reported that TSPO imaging has potential in measuring macrophage levels in tumours, whereas Zheng et al [7] reported on a low lesion-to-background uptake with [18F]DPA-714 in several models for cancer and inflammation
In the current study we have shown that RT increases the [18F]F-DPA uptake in two different head and neck squamous cell carcinoma (HNSCC) xenograft models (FaDu and Cal33), as well as in FaDu cells
Summary
Translocator protein (TSPO)-targeting positron emission tomography (PET) imaging is currently mainly used for imaging neurodegenerative diseases [1] and brain gliomas [2] as TSPO is considered a biomarker of neuroinflammation and microglial activation. Apart from brain gliomas, only a few preclinical studies have evaluated TSPO-PET tracers in peripherally located tumours [5,6,7,8,9]. Many of these reports focused on evaluating the relationship between tracer uptake and tumour inflammation and/ or levels of macrophages [5,6,7,8]. Several studies [5, 6, 8] have reported that TSPO imaging has potential in measuring macrophage levels in tumours, whereas Zheng et al [7] reported on a low lesion-to-background uptake with [18F]DPA-714 in several models for cancer and inflammation. TSPO protein and mRNA expression, as well as tumour-associated macrophages (TAMs), were assessed
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