Oncotarget

Research Papers:

Non-invasive assessment of murine PD-L1 levels in syngeneic tumor models by nuclear imaging with nanobody tracers

Katrijn Broos, Marleen Keyaerts, Quentin Lecocq, Dries Renmans, Tham Nguyen, David Escors, Adrian Liston, Geert Raes, Karine Breckpot and Nick Devoogdt _

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Oncotarget. 2017; 8:41932-41946. https://doi.org/10.18632/oncotarget.16708

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Abstract

Katrijn Broos1,*, Marleen Keyaerts2,3,*, Quentin Lecocq1, Dries Renmans1, Tham Nguyen2,4, David Escors6, Adrian Liston7,8, Geert Raes4,5,*, Karine Breckpot1,* and Nick Devoogdt2,*

1Laboratory of Molecular and Cellular Therapy (LMCT), Vrije Universiteit Brussel, B-1090 Brussels, Belgium

2In Vivo Cellular and Molecular Imaging Laboratory (ICMI), Vrije Universiteit Brussel, B-1090 Brussels, Belgium

3Nuclear Medicine Department, UZ Brussel, B-1090 Brussels, Belgium

4Unit of Cellular and Molecular Immunology (CMIM), Vrije Universiteit Brussel, B-1050 Brussels, Belgium

5Myeloid Cell Immunology Laboratory, VIB Inflammation Research Center, 9052 Ghent, Belgium

6Immunomodulation Group, Navarrabiomed-Biomedical Research Centre, 31008 Pamplona, Navarra, Spain

7Department of Microbiology and Immunology, University of Leuven (KU Leuven), 3000 Leuven, Belgium

8VIB Center for Brain and Disease Research, 3000 Leuven, Belgium

*These authors contributed equally to this work

Correspondence to:

Nick Devoogdt, email: ndevoogd@vub.ac.be

Keywords: immune checkpoints, programmed death-1/programmed death-ligand 1, biomarker, nanobodies, SPECT/CT imaging

Received: January 21, 2017     Accepted: March 19, 2017     Published: March 30, 2017

ABSTRACT

Blockade of the inhibitory PD-1/PD-L1 immune checkpoint axis is a promising cancer treatment. Nonetheless, a significant number of patients and malignancies do not respond to this therapy. To develop a screen for response to PD-1/PD-L1 inhibition, it is critical to develop a non-invasive tool to accurately assess dynamic immune checkpoint expression. Here we evaluated non-invasive SPECT/CT imaging of PD-L1 expression, in murine tumor models with varying PD-L1 expression, using high affinity PD-L1-specific nanobodies (Nbs). We generated and characterized 37 Nbs recognizing mouse PD-L1. Among those, four Nbs C3, C7, E2 and E4 were selected and evaluated for preclinical imaging of PD-L1 in syngeneic mice. We performed SPECT/CT imaging in wild type versus PD-L1 knock-out mice, using Technetium-99m (99mTc) labeled Nbs. Nb C3 and E2 showed specific antigen binding and beneficial biodistribution. Through the use of CRISPR/Cas9 PD-L1 knock-out TC-1 lung epithelial cell lines, we demonstrate that SPECT/CT imaging using Nb C3 and E2 identifies PD-L1 expressing tumors, but not PD-L1 non-expressing tumors, thereby confirming the diagnostic potential of the selected Nbs. In conclusion, these data show that Nbs C3 and E2 can be used to non-invasively image PD-L1 levels in the tumor, with the strength of the signal correlating with PD-L1 levels. These findings warrant further research into the use of Nbs as a tool to image inhibitory signals in the tumor environment.


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