title: High-Resolution PET Imaging with Therapeutic Antibody-based PD-1/PD-L1 Checkpoint Tracers.
abstract: Checkpoint-blocking antibodies like those targeting the PD-1/PD-L1 pathway have revolutionized oncology. We developed radiotracers based on therapeutic checkpoint-blocking antibodies permitting sensitive and high-resolution PET imaging of both PD-1 and PD-L1 in immunocompetent mice. ImmunoPET of naive mice revealed similar overall expression patterns for PD-1 and PD-L1 in secondary lymphoid organs (spleen and lymph nodes). Interestingly, PD-L1 was also detected in brown adipose tissue (BAT), confirming the notion that BAT is immunologically relevant. Under pathophysiological conditions, strong expression of the receptor/ligand pair was also found in non-lymphoid tissues. Both were specifically detected in malignant tumors. PD-1 was readily detected after combined immunoradiotherapy causing massive tumor infiltration by PD-1+ lymphocytes. PD-L1 tracer uptake was reduced in PD-L1 knockout tumors. Moreover, monitoring the expression changes of PD-L1 in response to its main inducer, the effector T cell cytokine IFN-γ, revealed robust upregulation in the lung. This suggests that T cell responses in the lung, a vital organ continuously exposed to a variety of antigens, are strongly restrained by the PD-1 checkpoint. In turn, this could explain the association of PD-1 checkpoint inhibition with potentially fatal immune-mediated pneumonitis and partially also its efficacy in lung cancer.
authors.affiliation: 1. Department of Radiation Oncology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany.; 3. Faculty of Biology, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hettich
authors.affiliation: 2. Department of Nuclear Medicine, Medical Center - University of Freiburg, D-79106 Freiburg, Germany.; 3. Faculty of Biology, University of Freiburg, D-79104 Freiburg, Germany.
authors.forename: Friederike
authors.initials: F
authors.lastname: Braun
authors.affiliation: 2. Department of Nuclear Medicine, Medical Center - University of Freiburg, D-79106 Freiburg, Germany.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Bartholomä
authors.affiliation: 4. Department of Internal Medicine I, Medical Center - University of Ulm, D-89081 Ulm, Germany.
authors.forename: Reinhold
authors.initials: R
authors.lastname: Schirmbeck
authors.affiliation: 1. Department of Radiation Oncology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany.; 5. German Cancer Consortium (DKTK), D-79106 Freiburg, Germany.; 6. German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
mesh_terms: D000818:Animals; D000906:Antibodies / Q000008:administration & dosage*; D060890:B7-H1 Antigen / Q000032:analysis* / Q000276:immunology; D007155:Immunologic Factors / Q000008:administration & dosage*; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis* / Q000276:immunology
chemical_list: D000906:Antibodies; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D007155:Immunologic Factors; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor
keywords: PD-1/PD-L1 checkpoint; PET; antibody imaging.; non-invasive imaging