Targeted therapy against the programmed cell death ligand-1 (PD-L1) blockade holds considerable promise for the treatment of different tumor types; however, little effect has been observed against gliomas thus far. Effective glioma therapy requires a delivery vehicle that can reach tumor cells in the central nervous system, with limited systemic side effect. In this study, we developed a cyclic peptide iRGD (CCRGDKGPDC)-conjugated solid lipid nanoparticle (SLN) to deliver small interfering RNAs (siRNAs) against both epidermal growth factor receptor (EGFR) and PD-L1 for combined targeted and immunotherapy against glioblastoma, the most aggressive type of brain tumors. Building on recent studies showing that radiation therapy alters tumors for enhanced nanotherapeutic delivery in tumor-associated macrophage-dependent fashion, we showed that low-dose radiation primes targeted SLN uptake into the brain tumor region, leading to enhanced downregulation of PD-L1 and EGFR. Bioluminescence imaging revealed that ra...

/pdf/radiation-induced-targeted-nanoparticle-based-gene-delivery-2e5efaw0zc.pdf

Radiation-Induced Targeted Nanoparticle-Based Gene Delivery for Brain Tumor Therapy

Background: The latest immunotherapy, used in the treatment of non-small cell lung cancer (NSCLC), uses monoclonal antibodies directed against programmed death ligand 1 (PD-L1) to inhibit its interaction with the PD-1 receptor. Elevated levels of PD-L1 expression were observed on NSCLC cells. The association between PD-L1 expression and clinicopathological features is still unclear. Therefore, we examined this relationship and also compare PD-L1 expression levels with Ki-67, p63 and TTF-1. Methods: 866 samples of NSCLCs were used to prepare tissue microarrays (TMAs) on which immunohistochemical (IHC) reactions were performed. Changes in the level of CD274 (PD-L1) gene expression in 62 NSCLC tumors were tested in relation to 14 normal lung tissues by real-time PCR reactions (RT-PCR). Results: PD-L1 expression was observed in 32.6% of NSCLCs. PD-L1 expression was increased in higher malignancy grades (G) (p < 0.0001) and in higher lymph node status (pN) (p = 0.0428). The patients with low PD-L1 expression had longer overall survival compared to the group with high expression (p = 0.0332) in adenocarcinoma (AC) only. Conclusions: PD-L1 expression seems to be associated with increased tumor proliferation and aggressiveness as well as shorter patient survival in NSCLC, predominantly in the AC group.

Role of PD-L1 Expression in Non-Small Cell Lung Cancer and Their Prognostic Significance according to Clinicopathological Factors and Diagnostic Markers.

Exosomes are small extracellular vesicles released by cells for cell-cell communication. They play important roles in cancer development, metastasis, and drug resistance. Exosomal proteins have been demonstrated by many studies as promising biomarkers for cancer screening, diagnosis, and monitoring. Among many detection techniques, surface plasmon resonance (SPR) is a highly sensitive, label-free, and real-time optical detection method. Commercial prism-based wavelength/angular-modulated SPR sensors afford high sensitivity and resolution, but their large footprint and high cost limit their adaptability for clinical settings. Recently, a nanoplasmonic exosome (nPLEX) assay was developed to detect exosomal proteins for ovarian cancer diagnosis. However, comparing with conventional SPR biosensors, the broad applications of nanoplasmonic biosensors are limited by the difficult and expensive fabrication of nanostructures. We have developed an intensity-modulated, compact SPR biosensor (25 cm × 10 cm × 25 cm) which uses a conventional SPR sensing mechanism and does not require nanostructure fabrication. Calibration from glycerol showed that the compact SPR biosensor offered sensitivity of 9.258 × 103%/RIU and resolution of 8.311 × 10-6 RIU. We have demonstrated the feasibility of the compact SPR biosensor in lung cancer diagnosis using exosomal epidermal growth factor receptor (EGFR) and programmed death-ligand 1 (PD-L1) as biomarkers. It detected a higher level of exosomal EGFR from A549 nonsmall cell lung cancer (NSCLC) cells than BEAS-2B normal cells. With human serum samples, the compact SPR biosensor detected similar levels of exosomal EGFR in NSCLC patients and normal controls, and higher expression of exosomal PD-L1 in NSCLC patients than normal controls. The compact SPR biosensor showed higher detection sensitivity than ELISA and similar sensing accuracy as ELISA. It is a simple and user-friendly sensing platform, which may serve as an in vitro diagnostic test for cancer.

https://par.nsf.gov/servlets/purl/10073317

Sensitive Detection of Exosomal Proteins via a Compact Surface Plasmon Resonance Biosensor for Cancer Diagnosis.

Since the publication of this paper, the authors noticed that Corentin Richard was not credited as contributing equally to the paper. He should be considered as a joint first author with Jean-David Fumet.

/pdf/prognostic-and-predictive-role-of-cd8-and-pd-l1-4tptej8yui.pdf

Prognostic and predictive role of CD8 and PD-L1 determination in lung tumor tissue of patients under anti-PD-1 therapy

Immune checkpoint inhibitors in epidermal growth factor receptor mutant non-small cell lung cancer: Current controversies and future directions

Although many studies have addressed the prognostic value of programmed cell death-ligand 1 (PD-L1) expression in lung cancer, the results remain controversial. A systematic search of the PubMed, EMBASE, and Cochrane Library databases was performed to identify the correlation between PD-L1 expression and driver mutations and overall survival (OS). This meta-analysis enrolled a total of 11,444 patients for 47 studies, and the pooled results showed that increased PD-L1 expression was associated with poor prognosis (HR = 1.40, 95% CI: 1.19–1.65, P < 0.001). In subgroup analysis stratified according to histology types, the pooled results demonstrated that increased PD-L1 expression was an unfavorable prognostic factor for non-small cell lung cancer (NSCLC) (HR = 1.26, 95% CI: 1.05–1.52, P = 0.01) and pulmonary lymphoepithelioma-like carcinoma (LELC) (HR = 3.04, 95% CI: 1.19–7.77, P = 0.02), rather than small cell lung cancer (SCLC) (HR = 0.62, 95% CI: 0.27–1.39, P = 0.24). The pooled ORs indicated that PD-L1 expression was associated with gender, smoking status, histology, differentiation, tumour size, lymph nodal metastasis, TNM stage and EGFR mutation. However, PD-L1 expression was not correlated with ALK rearrangement and KRAS mutations.

/pdf/pd-l1-expression-in-lung-cancer-and-its-correlation-with-12hz3o55tu.pdf

PD-L1 expression in lung cancer and its correlation with driver mutations: a meta-analysis

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PD-L1 expression in lung cancer and its correlation with driver mutations: a meta-analysis