Prediction of Responsiveness to PD-L1/PD-1 Inhibitors Using miRNA Profiles Associated With PD-L1 Expression in Lung Adenocarcinoma and Squamous Cell Carcinoma.

MicroRNAs (miRNAs) regulate programmed cell death ligand 1 (PD-L1) and play a crucial role in tumor immune response. However, the relationship between miRNA expression patterns and PD-L1 remains unclear in both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). We investigated PD-L1-related miRNAs that can predict treatment response in patients treated with PD-L1/PD-1 inhibitors. We selected miRNAs that were correlated with PD-L1 expression within the LUAD and LUSC datasets obtained from The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC). We validated whether the miRNA profile could be used to predict the prognosis of patients treated with PD-L1/PD-1 inhibitors. Based on four public datasets, we selected 66 and 23 miRNAs associated with PD-L1 expression in LUAD and LUSC, respectively. From the above miRNAs, we identified 5 miRNAs in LUSC and 1 miRNA in LUAD that could predict the response to PD-L1/PD-1 inhibitors in a validation set of patients treated with PD-L1/PD-1 inhibitors. In LUSC, the miRNA profile exhibited a high predictive capability for the response to PD-L1/PD-1 treatment [area under the curve (AUC)=0.963] and accurately predicted prognosis (p=0.031). In LUAD, the miRNA profile was relatively less predictive than in LUSC (AUC=0.691 and p=0.213). Additionally, we observed variations in the PD-L1-associated miRNA profiles, as well as in the associated pathways, between LUAD and LUSC. The PD-L1-associated miRNA profile may predict treatment response in LUSC patients treated with PD-L1/PD-1 inhibitors and help select the PD-L1/PD-1 inhibitor treatment group.

Koh YW ，Han JH ，Haam S ，Lee HW ... -  《-》

MiR-140-3p Improves Sensitivity to Docetaxel by Suppressing PD-L1/ABCG2/MVP Expression in Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) or lung squamous cell carcinoma (LUSC) accounts for the majority of non-small cell lung cancer (NSCLC), and overexpression of programmed death ligand 1 (PD-L1) in these cells is known to induce tumor immune evasion or drug resistance. However, detailed studies are needed to determine whether microRNAs (miRNAs) that reduce PD-L1 expression can suppress drug resistance in NSCLC. Kaplan Meier plotter and Receiver Operating Characteristic plotter were used to determine the effect of specific miRNAs on survival and chemotherapy response in NSCLC patients. Cell viability, colony formation and invasion assays, and qPCR analyses were also performed. The expression of miRNA-140-3p (miR-140-3p) was lower in LUAD patients, compared to the normal group, and low expression of miR-140-3p was associated with poor survival of LUAD patients, but not in LUSC. The miR-140-3p mimic inhibited proliferation, colony formation, and invasion of LUAD cells. Interestingly, the expression of miR-140-3p was significantly lower in the group of LUAD patients who did not respond to docetaxel. In LUAD cells, combined treatment with miR-140-3p and docetaxel significantly reduced cell viability as well as the expression of ABCG2 and MVP, genes associated with drug resistance, compared to either treatment alone. Additionally, combined injection of miR-140-3p mimic and docetaxel significantly inhibited tumor growth compared to treatment with docetaxel alone. These results suggest that the high expression of miR-140-3p in LUAD is correlated with good patient prognosis and may contribute to the treatment of LUAD, especially by increasing responsiveness to docetaxel.

Kwon M ，Lim D ，Park J ，Gil W ，Jung J ，Jung S ，Kim C ，Go M ，Cheong YH ，Park HS ，Eom YB ，Park SA ... -  《-》

System analysis of FHIT in LUAD and LUSC: The expression, prognosis, gene regulation network, and regulation targets.

Situ Y ，Gao R ，Lei L ，Deng L ，Xu Q ，Shao Z ... -  《-》

PD-L1 and PD-L2 expression correlated genes in non-small-cell lung cancer.

Larsen TV ，Hussmann D ，Nielsen AL 《Cancer Communications》

PD-L1 and CD47 co-expression predicts survival and enlightens future dual-targeting immunotherapy in non-small cell lung cancer.

Recent studies have indicated that programmed cell death-ligand 1 (PD-L1) and cluster of differentiation 47 (CD47) play an essential role in tumor immune evasion and may serve as potential targets for combined immunotherapy. The aim of our study was to evaluate the PD-L1/CD47 expression status in lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD), and explore its survival impact and relevance with the immune microenvironment. The specimens from 190 LUSC and 240 LUAD patients who underwent intent-to-treat surgeries were retrospectively collected for immunohistochemistry assays of PD-L1, CD47, cluster of differentiation 8 (CD8), and cluster of differentiation 68 (CD68). A total of 96 (22.3%) and 296 (68.8%) cases were positive for PD-L1 and CD47 expression, respectively, and 80 (18.6%) of them demonstrated the co-expression of PD-L1/CD47. The rate of PD-L1/CD47 co-expression was 23.7% in LUSC, significantly higher than the 14.6% in LUAD (p = 0.018). The median overall survival (OS) for all patients was 55.9 months (range 2.0-146.0 months). The univariate analysis showed that patients with positive CD47 expression (LUSC p = 0.003, LUAD p = 0.036) and PD-L1/CD47 co-expression (LUSC p = 0.023, LUAD p = 0.004) exhibited significantly worse prognosis. The multivariate analysis demonstrated that PD-L1/CD47 co-expression was an independent prognostic factor for OS (LUSC hazard ratio [HR] 1.922, 95% CI 1.245-2.969, p = 0.003; LUAD HR 1.549, 95% CI 1.015-2.364, p = 0.043). PD-L1/CD47 co-expression was associated with high CD8-positive T-lymphocyte density in LUSC (p = 0.004) and LUAD (p = 0.043), and with high CD68-positive macrophage density in LUSC (p = 0.026). PD-L1/CD47 co-expression was an independent prognostic factor for LUSC and LUAD patients and may serve as a potential predictive biomarker for combined dual-targeting immunotherapy.

Yang Z ，Peng Y ，Guo W ，Xu J ，Li L ，Tian H ，Li R ，Liu L ，Tan F ，Gao S ，He J ... -  《-》