High expression of PD-L1 mainly occurs in non-small cell lung cancer patients with squamous cell carcinoma or poor differentiation.

Lung cancer is one of the most lethal cancers worldwide, but studies have shown that the higher the expression of programmed cell death protein 1 ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), the more likely it will benefit from anti-PD-L1 immunotherapy. The purpose of our study was to collect and analyze abundant clinical samples in order to provide evidence for clinicians and patients who might consider anti-PD-L1 immunotherapy while jointly formulating treatment plans. On the one hand, we obtained cases from The Cancer Genome Atlas (TCGA) database, including 498 lung squamous cell cancer (LUSC) patients and 515 lung adenocarcinoma (LUAD) patients. We studied the lung caner driver gene in LUSC and LUAD. On the other hand, PD-L1 expression was detected in lung cancer tissues of 1,008 NSCLC patients with immunohistochemistry staining (IHC), and we studied the correlation between PD-L1 protein expression and clinicopathological characteristics. PD-L1 expression was higher in LUSC than in LUAD at the mRNA level. In univariate analysis, PD-L1 expression at the protein level was higher in patients who were males, were LUSC, were smokers, had a tumor diameter >3 cm, had poor differentiation, or had stages III~IV disease. In multivariate analysis, PD-L1 expression was higher in patients who were LUSC or in poor differentiation. In term of protein level, PD-L1 expression was higher in NSCLC patients who were LUSC or in poor differentiation. We recommend that PD-L1 IHC detection can be routinely performed in such populations that are likely to benefit most from PD-L1 immunotherapy.

Liu LU ，Xie B ，Zhu W ，He Q ，Zhou J ，Liu S ，Tao Y ，Xiao D ... -  《-》

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 ... -  《-》

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 ... -  《-》

Hypoxia-related lncRNAs to build prognostic classifier and reveal the immune characteristics of EGFR wild type and low expression of PD-L1 squamous and adenocarcinoma NSCLC.

Recently, the development and application of targeted therapies like tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) have achieved remarkable survival benefits in non-small cell lung cancer (NSCLC) treatment. However, epidermal growth factor receptor (EGFR) wild type and low expression of programmed death-ligand 1 (PD-L1) NSCLC remain unmanageable. Few treatments for these patients exist, and more side effects with combination therapies have been observed. We intended to generate a hypoxia-related lncRNAs (hypolncRNAs) classifier that could successfully identify the high-risk patients and reveal its underlying molecular immunology characteristics. By identifying the bottom 25% PD-L1 expression level as low expression of PD-L1 and removing EGFR mutant samples, a total of 222 lung adenocarcinoma (LUAD) and lung squamous carcinoma (LUSC) samples and 93 adjacent non-tumor samples were finally extracted from The Cancer Genome Atlas (TCGA). A 0 or 1 matrix was constructed by cyclically pairing hypoxia-related long non-coding RNAs (hypolncRNAs) and divided into the train set and test set. The univariate Cox regression analysis determined the prognostic hypolncRNAs pairs. Then, the prognostic classifier contained nine hypolncRNAs pairs which were generated by Lasso regression and multivariate Cox analysis. It successfully stratified EGFR wild type and low expression of PD-L1 squamous and adenocarcinoma NSCLC (double-negative LUAD and LUSC) patients into the high- and low-risk groups, whose accuracy was proved by the time-dependent receiver operating characteristic (ROC) curve. Furthermore, diverse acknowledged immunology methods include XCELL, TIMER, QUANTISEQ, MCPcounter, EPIC, CIBERSORT-ABS, CIBERSORT, and the single-sample gene set enrichment analysis (ssGSEA) revealed its underlying antitumor immunosuppressive status in the high-risk patients. It is noteworthy that hypolncRNAs are associated with the survival of double-negative LUAD and LUSC patients, for which the possible mechanism is inhibiting the antitumor immune process.

Zhao F ，Wang M ，Zhu J 《-》