This is a summary of Deciphering sources of PET signals in the tumor microenvironment of glioblastoma at cellular resolution. Laura M. Bartos, Sabrina V. Kirchleitner, Zeynep Ilgin Kolabas, Stefanie Quach, Alexander Beck, Julia Lorenz, Jens Blobner, Stephan A. Mueller, Selin Ulukaya, [...], and Matthias Brendel. Science Advances, 2023, DOI: https://www.science.org/doi/10.1126/sciadv.adi8986

The challenge

Glioblastoma is one of the most malignant types of brain cancer in adults. It is characterized by its resistance to current immunotherapies. To better understand this type of tumor and develop more effective therapies, researchers focus on the tumor microenvironment – the tissue in which the tumor develops and grows – and especially on the immune cells. However, identifying immune cells has been a major challenge to date. One possibility is using positron emission tomography. In a PET scan, small amounts of radioactively labeled substances, so-called tracers, are injected in a vein and distributed in the body and the brain cells. They are made visible by a PET camera. This makes the biomarker perceptible in the tissue and provides insights into the activity and role of the immune cells. Nonetheless, the precise interpretation of PET signals is challenged by the heterogeneity of underlying cell types.

Our approach

We developed a new method to resolve the PET tracer signals at the cellular level. The method consists of radiotracer injection and subsequent isolation and measurement of the cells. This makes it possible to assign PET tracer signals at the cellular level in glioblastomas and can thus unravel the role of immune cells. We also used 3D histology, a three-dimensional examination of a tissue sample, to examine the tumor tissue in its entirety and classify the PET signals in the context of the detected cell numbers. This allowed us to see whether the PET signal can be explained by the cellular uptake or to what extent other factors, such as a damaged blood-brain barrier, also contribute to the signal.

Our findings

We found that the translocator protein is not a specific biomarker for immune cells but that most of the PET signals are related to tumor cells. We were able to detect around 90 percent of the more than 7,000 proteins analyzed in both tumor cells and immune cells. We were particularly interested in which proteins only occur in immune cells: we identified target proteins that were strongly increased in immune cells in diseased tissue but not in tumor cells.

The implications

Our findings can lead to the development of new radiotracers to track the reaction of immune cells. Overall, the method is not only valuable for the diagnosis and treatment of brain tumors – we can also use PET to decode all signals that can be generated in the brain. Our research group currently uses it for Alzheimer’s research to study the deposition of the tau protein.

Creating SyNergies

This research in SyNergy was led by Matthias Brendel’s team in collaboration with SyNergy members Stefan Lichtenthaler (proteomic)s, Jochen Herms (immunohistochemistry) and Ali Ertürk (3D histology).