Combined PET imaging of the inflammatory tumor microenvironment identifies margins of unique radiotracer uptake.

Zinnhardt B, Pigeon H, Thézé B, Viel T, Wachsmuth L, Fricke IB, Schelhaas S, Honold L, Schwegmann K, Wagner S, Faust A, Faber C, Kuhlmann MT, Hermann S, Schäfers M, Winkeler A, Jacobs AH.

Abstract

The tumor microenvironment is highly heterogeneous. For gliomas, the tumor-associated inflammatory response is pivotal to support growth and invasion. Factors of glioma growth, inflammation, and invasion, such as the translocator protein (TSPO) and matrix metalloproteinases (MMP), may serve as specific imaging biomarkers of the glioma microenvironment. In this study, non-invasive imaging by positron emission tomography (PET) with [18F]DPA-714 (TSPO) and [18F]BR-351 (MMP) was used for assessment of localization and quantification of the expression of TSPO and MMP. Imaging was performed in addition to established clinical imaging biomarker of active tumor volume ([18F]FET) in conjunction with magnetic resonance imaging (MRI). We hypothesized that each imaging biomarker revealed distinct areas of the heterogeneous glioma tissue in a mouse model of human glioma. Tracers were found to be increased 1.4-1.7 fold with [18F]FET showing the biggest volume as depicted by a thresholding-based, volumes of interest (VOI) analysis. Tumor areas, which could not be detected by a single tracer and/or MRI parameter alone, were measured. Specific compartments of [18F]DPA-714 (14%) and [18F]BR-351 (11%) volumes along the tumor rim could be identified. [18F]DPA-714 (TSPO) and [18F]BR-351 (MMPs) matched with histology. Glioma-associated microglia/macrophages (GAM) were identified as TSPO and MMP sources. Multi-tracer and multi-modal molecular imaging approaches may allow us to gain important insights into glioma-associated inflammation (GAM, MMP). Moreover, this non-invasive technique enables characterization of the glioma microenvironment with respect to the disease-driving cellular compartments at the various disease stages.