PET imaging of immune checkpoint proteins in oncology

Despite the remarkable clinical successes of immune checkpoint inhibitors (ICIs) in various advanced cancers, response is still limited to a subset of patients that generally exhibit tumoral expression of immune checkpoint (IC) proteins. Development of biomarkers assessing the expression of such ICs is therefore a major challenge nowadays to refine patient selection and improve therapeutic benefits. Positron emission tomography (PET) imaging using IC-targeted radiolabeled monoclonal antibodies (immunoPET) provides a non-invasive and whole-body visualization of in vivo IC biodistribution. As such, PET imaging of ICs may serve as a robust biomarker to predict and monitor responses to ICIs, complementing the existing immunohistochemical techniques. Besides monoclonal antibodies, other PET radioligand formats, ranging from antibody-derived fragments to small proteins, have gained increasing interest owing to their faster pharmacokinetics and enhanced imaging characteristics. We provide an overview of the various strategies investigated so far for PET imaging of ICs in preclinical and clinical studies, emphasizing their benefits and limitations. Moreover, we discuss various parameters to consider for designing optimized and best-suited PET radioligands.