Abstract
Preclinical studies demonstrated that radiation up-regulates PD-L1 expression in tumor cells, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. However this has not been validated in patients with non-small cell lung cancer due to the difficulty to obtain serial biopsies. Measuring PD-L1 expression in circulating tumor cells (CTCs), may allow real-time monitoring of immune activation in tumor. In this study, whole blood from non-metastatic NSCLC patients was collected before, during, and after radiation or chemoradiation using a microfluidic chip. PD-L1 expression in CTCs was assessed by immunofluorescence and qPCR and monitored through the course of treatment. Overall, PD-L1(+) CTCs were detected in 25 out of 38 samples (69.4%) with an average of 4.5 cells/ml. After initiation of radiation therapy, the proportion of PD-L1(+) CTCs increased significantly (median 0.7% vs. 24.7%, P < 0.01), indicating up-regulation of PD-L1 in tumor cells in response to radiation. In addition, patients positive for PD-L1 (≥5% of CTCs positive for PD-L1) at baseline had shorter PFS. Gene expression analysis revealed that higher levels of PD-L1 were associated with poor prognosis. Therefore, CTCs can be used to monitor dynamic changes of PD-L1 during radiation therapy which is potentially prognostic of response to treatment.
Highlights
Recent clinical trials using PD-1/PD-L1 inhibitors have shown improved overall survival in NSCLC patients[8,9,10]
We developed a nanomaterial-based microfluidic platform for circulating tumor cells (CTCs) isolation, the graphene oxide (GO) Chip, which consists of a microfluidic chamber and a substrate coated with GO nanosheets where the antibodies are tethered[27]
To test the performance of the GO device for NSCLC CTC capture, varying number of lung cancer cell lines, H1650 and H441 cells were labeled with green cell tracker dye and spiked into 1 ml of whole blood obtained from healthy donors
Summary
Recent clinical trials using PD-1/PD-L1 inhibitors have shown improved overall survival in NSCLC patients[8,9,10]. Growing evidence demonstrates that radiation can elicit an adaptive immune response, but the immunogenic effect of radiation could be undermined by the upregulation of PD-L1 in tumor microenvironment[15] This provides the primary rationale for combining PD-1/PD-L1 inhibitors with radiation[16,17]. We developed a nanomaterial-based microfluidic platform for CTC isolation, the graphene oxide (GO) Chip, which consists of a microfluidic chamber and a substrate coated with GO nanosheets where the antibodies are tethered[27]. This technology takes advantage of the increased surface area afforded by GO to achieve higher antibody coating density, and improved sensitivity for CTC capture. We evaluated whether PD-L1 (+) CTC counts and PD-L1 mRNA expression level correlates with patient outcomes
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