Theranostics 2016; 6(10):1629-1640. doi:10.7150/thno.15253

Research Paper

High-Resolution PET Imaging with Therapeutic Antibody-based PD-1/PD-L1 Checkpoint Tracers

Michael Hettich1,3, Friederike Braun2,3, Mark D. Bartholomä2, Reinhold Schirmbeck4, Gabriele Niedermann1,5,6 ✉

1. Department of Radiation Oncology, Medical Center - University of Freiburg, D-79106 Freiburg, Germany.
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.
4. Department of Internal Medicine I, Medical Center - University of Ulm, D-89081 Ulm, Germany.
5. German Cancer Consortium (DKTK), D-79106 Freiburg, Germany.
6. German Cancer Research Center (DKFZ), D-69120 Heidelberg, Germany.

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.

Keywords: non-invasive imaging, PET, PD-1/PD-L1 checkpoint, antibody imaging.

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How to cite this article:
Hettich M, Braun F, Bartholomä MD, Schirmbeck R, Niedermann G. High-Resolution PET Imaging with Therapeutic Antibody-based PD-1/PD-L1 Checkpoint Tracers. Theranostics 2016; 6(10):1629-1640. doi:10.7150/thno.15253. Available from http://www.thno.org/v06p1629.htm