Visualizing dynamic changes in PD-L1 expression in non-small cell lung carcinoma with radiolabeled recombinant human PD-1.

Abstract

Tumor heterogeneity limits the predictive value of PD-L1 expression and influences the outcomes of the immunohistochemical assay for therapy-induced changes in PD-L1 levels. This study aimed to determine the predictive value of PD-L1 for non-small cell lung carcinoma (NSCLC), thereby developing imaging agents to non-invasively image and examine the effect of the therapeutic response to PD-L1 blockade therapy. A cohort of 102 patients with lung cancer was analyzed, and the prognostic significance of PD-L1 expression level was investigated. Recombinant human PD-1 ECD protein (rhPD1) was expressed, purified, and labeled with ⁶⁴Cu for the evaluation of PD-L1 status in tumors. Mice subcutaneously bearing PD-L1 high-expressing tumor HCC827 and PD-L1 low-expressing tumor A549 were used to determine tracer-target specificity and examine the effect of therapeutic response to PD-L1 blockade therapy. PD-L1 was proved to be a good prognosis marker for NSCLC, and its expression was correlated with the histology of NSCLC. PET imaging revealed high tumor accumulation of ⁶⁴Cu-NOTA-rhPD1 in HCC827 tumors (9.0 ± 0.5%ID/g), whereas it was 3.2 ± 0.4%ID/g in A549 tumors at 3 h post-injection. The lower tumor uptake (3.1 ± 0.3%ID/g) of ⁶⁴Cu-labeled denatured rhPD1 in HCC827 tumors at 3 h post-injection (p < 0.001) demonstrated the target specificity of ⁶⁴Cu-NOTA-rhPD1. Furthermore, PET showed that ⁶⁴Cu-NOTA-rhPD1 sensitively monitored treatment-related changes in PD-L1 expression, and seemed to be superior to [¹⁸F]FDG. We identified PD-L1 as a good prognosis marker for surgically resected NSCLC and developed the PET tracer ⁶⁴Cu-NOTA-rhPD1 with high target specificity for PD-L1.