PD-L1 detection on circulating tumor-derived extracellular vesicles (T-EVs) from patients with lung cancer

Abstract

Background: Recent breakthroughs in therapies with immune checkpoint inhibitors (ICIs) have revolutionized the treatment of lung cancer. However, only 15-25% of patients respond to the ICIs therapy, and methods to identify those responsive patients are currently a hot research topic. PD-L1 expression measured on tumor tissues using immunohistochemistry (IHC) was approved as one of the companion diagnostic methods, but it is invasive and cannot be used to monitor dynamic changes in PD-L1 expression during treatments.Methods: In this study, we developed an Epcam-PD-L1 extracellular vesicle (EV) detection prototype using the Simoa platform. This assay detected PD-L1 expression levels on tumor-derived exosomes from the lung cancer cell lines A549 and SK-MES1. In addition, 35 plasma samples from patients with lung cancer were tested with this assay and the results were compared to the tissue PD-L1 expression levels represented by the tumor proportion score (TPS). Results: PD-L1 TPS-positive patients (≥1% IHC TPS) had significantly higher Simoa Epcam-PD-L1 signals than TPS-negative patients (<1% IHC TPS, P=0.026). The Simoa Epcam-PD-L1 area under curve (AUC) reached 0.776, with a sensitivity of 92.86% and a specificity of 71.43%. When PD-L1 TPS-positive patients were defined as having an IHC TPS ≥10%, the greatest difference in Epcam-PD-L1 signals was observed between IHC TPS-positive and IHC TPS-negative groups (P=0.0024) and the Simoa Epcam-PD-L1 AUC reached 0.832. Finally, the Spearman's correlation coefficient showed a significant correlation between the TPS and Simoa Epcam-PD-L1 signals (0.428, P=0.0104).Conclusions: Based on our results, our Simoa Epcam-PD-L1 EV detection assay is a potential liquid biopsy method to predict the PD-L1 expression level in patients with lung cancer.

Advancing microfluidic diagnostic chips into clinical use: a review of current challenges and opportunities

“…Digital assays have demonstrated utility as a platform for the ultrasensitive detection of proteins 10,37,48 and nucleic acids, 49,50 as well as the analysis of single cells 51,52 and single exosomes. [53][54][55][56]104 dELISA has been commercialized by Quanterix (Fig. 3c) and has found utility in several clinical applications, including traumatic brain injury and cancer diagnostics.…”

Molecular Docking and Intracellular Translocation of Extracellular Vesicles for Efficient Drug Delivery

“…In a mouse model of melanoma that closely mimics human cancer, the injection of PDL-1-coated exosomes promoted tumour growth and reduced the number of T cells and other immune cells in and around the tumour ( Figure 1 ) [ 162 , 173 , 189 , 190 , 191 , 192 ]. In addition, exosomes carrying PD-L1 have been identified in blood samples of patients with a history of breast cancer, melanoma, or lung cancer who had received treatments for their respective diseases [ 193 , 194 , 195 ].…”

“…Melanoma elicits a particularly strong immune response, and multiple immune checkpoint inhibitors have been approved by the US Food and Drug Administration for the treatment of melanoma [ 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 ]. Interestingly, based on PD-L1 levels in exosomes, patients who are most likely to respond to checkpoint inhibitors can be identified and the response to these drugs can be evaluated [ 162 , 194 , 196 , 197 , 198 , 199 ]. For example, compared to patients with high exosomal PD-L1 levels before treatment, those with lower levels responded remarkably better to treatments with the checkpoint inhibitor pembrolizumab (Keytruda), which can block PD-1, the immune cell binding partner of PD-L1 [ 185 , 196 , 198 , 200 , 201 , 202 , 203 , 204 , 205 ].…”

Anti-Cancer Role and Therapeutic Potential of Extracellular Vesicles

“…EVs collected from saliva may be useful for the diagnosis of lung cancer [ 192 , 193 , 194 ]. It has been reported that the contents of EVs collected from serum, such as miR-200, lipocalin-2 [ 86 ], miR-505-5p [ 91 ], ubiquitin C-terminal hydrolase-L1 (UCHL1) [ 88 ], cell-free DNA [ 82 , 83 ], and proteins [ 195 , 196 , 197 , 198 , 199 ], are useful for the diagnosis of lung cancer. MiR-193a-5p, and miR-551b-5p have been suggested as biomarkers of malignant pleural mesothelioma.…”