Sarah Verhoeff

141 Summary, general discussion and future perspectives In contrast, the over-expression of CAIX in ccRCC is the result of a mutational loss of the VHL gene. Multiple tracers have been tested for the purpose of CAIX imaging, both as a marker for CAIX-expressing ccRCC, as well as hypoxia imaging. The first radiotracer, chimeric monoclonal antibody G250 was able to image VHL-mutation-induced CAIX expression of ccRCC7. Later developments led to the chimeric variant chimeric girentuximab, which radiolabeled to zirconium-89 could visualize ccRCC lesions using PET8. PD-L1 Immune checkpoint inhibitors (ICI) targeting programmed death-1 (PD-1) or is ligand (PD-L1) were designed to restore antitumor immunity by blocking immunosuppressive checkpoints that are hijacked by cancer cells to avoid immune destruction9. Our knowledge of the regulatory mechanisms controlling PD-L1 expression and its interplay with other checkpoint molecules is incomplete, which complicates the interpretation of static ex vivo assessments10,11. The immunohistochemical assessment of PD-L1 expression on tumor biopsies has become clinical practice even though its predictive value is moderate at best. Nevertheless, it is being used as a biomarker to select patients for ICI treatment. PD-L1 is characterized by intra- and inter-tumoral heterogeneity, which is not accurately reflected by the current standard. Whole body PD-L1 PET-imaging allows for systemic assessment of PD-L1 expression of all tumor lesions and immune-related organs, as opposed to the immunohistochemical assessment of PD-L1 on a single tumor biopsy. However, the correct interpretation of tracer-accumulation is challenged by the physiological presence of PD-L1 on antigen-presenting cells and lymphoid tissues12. This also challenges a correlation with PD-L1 positive tumor cells by histochemistry to be found. 8