Abstract
BackgroundExosomes are 50–150 nm endocytic vesicles secreted by almost all type of cells that carry bioactive molecules from host. These small vesicles are considered to be novel cross-talk circuits established by tumor cells and tumor microenvironment. Previous studies have shown certain biological influence of exosomal programmed cell-death ligand 1 (Exo-PD-L1) on immune suppression and dysfunction. The aim of the current study was to investigate the impact of Exo-PD-L1 and soluble PD-L1 (sPD-L1) on non-small cell lung cancer (NSCLC) and explore the concordance between Exo-PD-L1 and PD-L1 expression in matched tumor tissues in NSCLC patients.Methods85 consecutive patients from April 2017 to December 2017 at General Hospital of Eastern Command Theatre who were primarily diagnosed with NSCLC and 27 healthy individuals were enrolled in this study. Two milliliters of whole blood samples were collected from each participant and further centrifuged. Exosomes were derived from serum using the commercial kit (Total Exosome Isolation Kit), which was further identified by Western blotting analysis (CD63/TSG101), transmission electron microscope analysis (TEM) and nanoparticle tracking analysis (NTA). Exosomes were next solubilized for Exo-PD-L1 detection by enzyme-linked immuno-sorbent assay (ELISA). PD-L1 expression in matched tissue were assessed by PD-L1 immunohistochemistry (IHC) (clone 28-8) assay. Tumor proportion score (TPS) ≥ 1% was deemed as “positive” in this study and TPS < 1% was deemed as “negative”. Written informed consent were obtained before acquisition of all data and biological sample. Data were analyzed using SPSS 20.0 and Graphpad Prism 5 software. Chi square test was conducted to estimate the correlation between Exo-PD-L1 levels, sPD-L1 levels, PD-L1 IHC profiles and clinicopathological features. For all analysis, a two-sided p < 0.05 was considered significant statistically.ResultsExo-PD-L1 levels were higher in NSCLC patients with advanced tumor stage, larger tumor size (> 2.5 cm) (p < 0.001), positive lymph node status (p < 0.05) and distant metastasis (p < 0.05). In contrast, sPD-L1 levels were not different between NSCLC patients and healthy donors, it was not correlated with any clinicopathologic features except for tumor size (> 2.5 cm) (p < 0.05). In addition, Exo-PD-L1 levels showed slight correlation with sPD-L1 levels (Spearman’s correlation at r = 0.3, p = 0.0027) while no correlation with PD-L1 IHC profiles was detected.ConclusionsIn conclusion, Exo-PD-L1, but not sPD-L1, was correlated with NSCLC disease progression, including tumor size, lymph node status, metastasis and TNM stage. However, Exo-PD-L1 was not associated with PD-L1 IHC status.
Highlights
Exosomes are 50–150 nm endocytic vesicles secreted by almost all type of cells that carry bioactive molecules from host
We aimed to explore the clinical significance of PD-L1 status both in serum-derived exosomes (Exo-PD-L1) and soluble PD-L1 in non-small cell lung cancer (NSCLC) patients
Concentration of Exo‐PD‐L1 and sPDL1 in serum of NSCLC The profile of Exo-PD-L1 was determined by enzyme-linked immuno-sorbent assay (ELISA) and the results showed that Exo-PD-L1 levels of I-II (15.90 ± 6.45 pg/ml serum) and III/IV NSCLC patients (21.10 ± 11.63 pg/ml serum) were considerably higher than that of healthy controls (15.91 ± 6.45 pg/ml serum) (p < 0.05 and p < 0.001, respectively) (Fig. 3a)
Summary
Exosomes are 50–150 nm endocytic vesicles secreted by almost all type of cells that carry bioactive molecules from host. These small vesicles are considered to be novel cross-talk circuits established by tumor cells and tumor microenvironment. Immunotherapy, principally represented by PD-1/ PD-L1 inhibitors, has improved the clinical outcome of advanced non-small cell lung cancer (NSCLC) [4,5,6]. Many NSCLC patients with PD-L1 IHC staining positive did not benefit from the immunotherapy. The reasons for this disappointing therapeutic response are unclear, but it is likely that the comprehensive mechanisms of PD-L1-driven pathway in TME, including significance of circulating PD-L1 are not fully understood
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