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Bioconjug Chem. 2019 May 15;30(5):1434-1441. doi: 10.1021/acs.bioconjchem.9b00178. Epub 2019 Apr 19.

Noninvasive Imaging and Quantification of Radiotherapy-Induced PD-L1 Upregulation with 89Zr-Df-Atezolizumab.

Author information

1
Medical Physics Department , University of Wisconsin-Madison , 1111 Highland Avenue , Madison , Wisconsin 53705 , United States.
2
Pharmaceutical Sciences Department , University of Wisconsin-Madison , 777 Highland Avenue , Madison , Wisconsin 53705 , United States.
3
Department of Medicine , University of Wisconsin-Madison , 1685 Highland Avenue , Madison , Wisconsin 53705 , United States.

Abstract

Immune checkpoint expression is highly dynamic, and combination treatments including radiotherapy can particularly modulate this expression. PET imaging using 89Zr-Df-atezolizumab can provide insight into the levels of PD-L1 variation following radiotherapy treatments. In vitro screening was used to monitor PD-L1 expression by lung cancer cells following radiotherapy. Mice bearing PD-L1+ (H460) or PD-L1- (A549) tumors were subjected to various external beam radiotherapy regimens and then imaged using 89Zr-Df-atezolizumab PET. ROI analysis and ex vivo biodistribution studies were employed to quantify tracer accumulations. H460 cells were found to have PD-L1 expression at baseline, and this expression increased following daily radiotherapy of 5 fractions of 2 Gy. PD-L1 expression could not be induced on A549 cells, regardless of radiotherapy regimen. The increase in PD-L1 expression in H460 tumors following fractionated radiotherapy could be imaged in vivo using 89Zr-Df-atezolizumab, with statistically significant higher tracer accumulation noted in fractionated H460 tumors over that in all other H460 or A549 groups after 72 h postinjection of the tracer. Significant accumulation of the tracer was also noted in other PD-L1+ organs, including the spleen and lymph nodes. Ex vivo staining of tumor tissues verified that tumor cells as well as tumor-infiltrating immune cells were responsible for increased PD-L1 expression after radiotherapy in tumor tissues. Overall, PD-L1 expression can be modulated with radiotherapy interventions, and 89Zr-Df-atezolizumab is able to noninvasively monitor these changes in preclinical models.

PMID:
30973703
PMCID:
PMC6521689
[Available on 2020-05-15]
DOI:
10.1021/acs.bioconjchem.9b00178

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