Programmed Death-ligand 1 Expression Levels Research Articles

PD-L1 strong expressions affect the clinical outcomes of osimertinib in treatment naïve advanced EGFR-mutant non-small cell lung cancer patients

The impact of strong Programmed Death-ligand 1 (PD-L1) expression on the clinical outcomes of osimertinib in treatment naïve advanced Epidermal Growth Factor Receptor (EGFR)-mutant Non-small Cell Lung Cancer (NSCLC) patients remains uncertain. We enrolled advanced NSCLC patients who harbored sensitizing EGFR mutation and were treated first-line with osimertinib between 2017 and 2021. The PD-L1 expression level was also tested. A total of 85 patients were included. The objective response rate to osimertinib was 78.9%, with the disease control rate being 90.8%. Median Progression-free Survival (PFS) was 22.1 months, while median Overall Survival (OS) was not reached (NR). Patients with the exon 19 deletion experienced better PFS than those with the exon 21 L858R mutation (NR vs 12.4 months, aHR 0.24 (95% CI, 0.10 to 0.57); p = 0.001). Seventy-one of these 85 patients had reported on their PD-L1 expression. Patients with a PD-L1 < 50% experienced longer PFS than patients with a PD-L1 ≧50% (26.5 vs 9.7 months, aHR 0.19 (95% CI, 0.06 to 0.67); p = 0.009). Additionally, patients with a PD-L1 < 50% experienced better OS than those with a PD-L1 ≧50% (NR vs 25.4 months, aHR 0.09 (95% CI, 0.01 to 0.70); p = 0.021). Strong expressions of PD-L1 in treatment naïve advanced EGFR-mutant NSCLC patients were associated with poor prognoses in those undergoing treatment with osimertinib as first-line therapy.

Early administration of durvalumab after chemoradiotherapy increased risk of pneumonitis in patients with locally advanced non-small cell lung cancer.

Durvalumab (Durva) administration after chemoradiation therapy (CRT) in locally advanced non-small-cell lung cancer (NSCLC) is the standard of care, associated with relatively prolonged progression-free (PFS) and overall survival. However, pneumonitis occurs in 73.6% of Japanese patients. This retrospective study aimed to identify factors associated with Durva efficacy and safety, specifically, the risk of pneumonitis. This study included data from 26 consecutive patients with locally advanced NSCLC who underwent CRT followed by Durva. The rates of adverse events and PFS were examined. The median PFS time was 15.6 months (95% confidence interval [CI]: 8.7-not available). Patients developed pneumonitis of grade 1, 2, 3, and 4 at the rate of 62%, 27%, 12%, and 0%, respectively. The median PFS time was 6.4 months for patients with programmed death ligand 1 (PD-L1) expression level of<50% and not reached for patients with PD-L1 expression level of ≥50% (hazard ratio [HR], 0.19; 95% CI: 0.04-0.89), which was significantly prolonged. The cumulative incidence of pneumonitis grade 2 or above was significantly higher when the time between the last day of thoracic radiotherapy (TRT) and the start of Durva therapy was within 14 days compared to >14 days (HR: 0.19; 95% CI: 0.06-0.59). This association was statistically significant in multivariate analysis. The initiation of Durva therapy within 14 days after TRT may increase the risk of pneumonitis grade 2 or above. Careful observation and suitable treatment are recommended.

Increased Abundances of CD16+ Non-Classical Monocytes Accompany with Elevated Monocytic PD-L1 and CD4+ T Cell Disturbances in Oropharyngeal Cancer.

Background: Patients with human papilloma virus (HPV)-related oropharyngeal cancer have a better prognosis than nonvirally associated patients, most likely because of better immune responses. Increased infiltration of T lymphocytes into the oropharyngeal tumor tissue has been observed, but the dynamics of circulating lymphocytes and monocytes are not fully understood. The aim of this study was to understand the population dynamics of circulating monocyte subsets in oropharyngeal cancer (OPC) patients with regard to the clinicopathological parameters and accompanying immunological consequences in view of the CD4/CD8 T cell subset composition, and the expression of checkpoint pathway proteins programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1). Materials and Methods: The abundance of circulating monocyte subsets and peripheral blood CD4/CD8 T cells of oropharyngeal cancer patients and their PD-L1 and PD-1 expression levels were analyzed by flow cytometry. Results: The studied oropharyngeal cancer patients revealed heterogeneous individual redistributions of CD14++CD16− (classical), CD14++CD16+ (intermediate), and CD14dim+CD16+ (nonclassical) monocyte subsets compared with healthy donors. These differences in monocyte subset alterations were independent in patients with TNM or HPV status but entailed further immunological consequences. Increased percentages of nonclassical monocytes significantly correlated with increased levels of monocytic PD-L1 expression. We observed significantly decreased levels of CD4+ effector T cells, which were accompanied by increased CD4+ effector memory T cells in OPC patients compared with healthy donors, each having a stronger effect in patients with decreased levels of classical monocytes. Conclusion: We conclude that oropharyngeal cancer, as a malignancy from a lymphoid-tissue-rich anatomical region, has a strong systemic impact on the differentiation and regulation of circulating innate and adaptive immune cells. Further comprehensive investigations are required for the possible future usability of the described immunological alterations as bioliquid parameters for prognosis or therapy response prediction.

Cost-Effectiveness of First-Line Nivolumab Plus Ipilimumab Combination Therapy in Advanced Non-Small-Cell Lung Cancer in Japan.

In Japan,indications for nivolumab have been expanded to include the combination therapy with ipilimumab in various cancers.This study aimed to evaluate the cost-effectiveness of combination therapy of nivolumab plus ipilimumab (NIV + IPI) for patients with advanced non-small-cell lung cancer (NSCLC), comparing it with platinum-doublet chemotherapy in Japanese settings. A partitioned survival model was developed to predict costs and quality-adjusted life-years (QALYs) in a NIV + IPI arm and a chemotherapy arm. Data on overall survival and progression-free survival were derived from the CheckMate227 trial. Cost estimates were based on a Japanese healthcare system perspective using real-world data from the JMDC claims database. Utilities were derived from published sources outside Japan. The incremental cost-effectiveness ratio (ICER) of NIV + IPI therapy compared with chemotherapy was estimated. A scenario analysis on the level of programmed death-ligand 1 (PD-L1) expression was conducted. In addition, sensitivity analyses were performed to assess the uncertainty in parameter settings. Compared with chemotherapy, NIV + IPI therapy incurred an additional cost of USD102,623 and conferred an additional 1.007 QALY, which resulted in an ICER of USD101,950/QALY gained. Contrary to prior expectations, the ICER of patients with a PD-L1 expression level ≥ 1% was higher than that of patients with a PD-L1 expression level < 1% (USD145,868/QALY and USD127,737/QALY, respectively). Sensitivity analyses showed a relatively robust result with the ICERs remaining higher than a Japanese price adjustment threshold of USD75,000/QALY with a few exceptions. The combination of NIV + IPI as first-line therapy would not be cost effective under a willingness-to-pay threshold of USD75,000/QALY from the perspective of the Japanese healthcare system.

An individual nomogram can reliably predict tumor spread through air spaces in non-small-cell lung cancer

BackgroundTumor spread through air spaces (STAS) has been shown to adversely affect the prognosis of lung cancer. The correlation between clinicopathological and genetic features and STAS remains unclear.MethodWe retrospectively reviewed 3075 NSCLC patients between2017-2019. We evaluated the relationship between STAS and patients’ clinicopathological and molecular features. The chi-square test was performed to compare categorical variables. Univariate analysis and multivariate logistic regression analysis were performed to investigate the association of clinical factors with STAS. A nomogram was formulated to predict the presence of STAS.ResultsSTAS was identified in 617 of 3075 patients (20.07%). STAS was significantly related to sex (p < 0.001), smoking (p < 0.001), CEA (p < 0.001), differentiation (p < 0.001), histopathological type (p < 0.001), lymphatic vessel invasion (p < 0.001), pleural invasion (p < 0.001), T stage (p < 0.001), N stage (p < 0.001), M stage (p < 0.001), and TNM stage (p < 0.001). STAS was frequently found in tumors with wild-type EGFR (p < 0.001), KRAS mutations (p < 0.001), ALK rearrangements (p < 0.001) or ROS1 rearrangements (p < 0.001). For programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1), STAS was associated with PD-L1 expression level in tumor cells (p < 0.001) or stromal cells (p < 0.001), while PD-1 only in stromal cells (p < 0.001). Multivariable analyses demonstrated significant correlations between STAS and CEA level (p < 0.001), pathological grade (p < 0.001), lymphatic vessel invasion (p < 0.001), pleural invasion (p = 0.001), and TNM stage (p = 0.002). A nomogram was formulated based on the results of the multivariable analysis.ConclusionsTumor STAS was associated with several invasive clinicopathological features. A nomogram was established to predict the presence of STAS in patients with NSCLC.

Overexpression of programmed death ligand 1 in refractory inflammatory bowel disease

Programmed death ligand 1 (PD-L1) dysregulation has been implicated in chronic inflammatory diseases, but its role in regulating intestinal mucosa inflammation is still unclear. The aim of this study was to assess PD-L1 expression in the intestinal mucosa of patients with refractory inflammatory bowel disease (IBD) compared to controls. We evaluated PD-L1 expression by immunohistochemistry in colectomy specimens of patients with ulcerative colitis (UC) and Crohn disease (CD) compared to controls. PD-L1 expression was assessed in colonic epithelium and inflammatory cells, along with the location of the inflammatory cells expressing PD-L1. All cases were stained with CD3, CD4, CD8, FOXP3, CD20, CD68, and CD90 immunostains to determine the types of cells expressing PD-L1. The UC group showed significantly higher PD-L1 expression in the colonic epithelium than both CD and control groups (both P<0.001), and CD was also significantly higher than the control group (P=0.004). Both UC and CD groups showed similar PD-L1 expression in the inflammatory infiltrate but significantly higher than the control group (both P<0.001). Among both IBD groups, higher IBD activity was associated with higher levels of PD-L1 expression in the colonic epithelium (P<0.05) and inflammatory infiltrate (P<0.001). When comparing PD-L1 expression to lineage-specific markers, CD3+, CD4+ T cells, CD68+ macrophages, and CD90+ colonic stromal cells appeared to be expressing PD-L1. These findings implicate a role for PD-L1 in the dysregulation of the immune response in refractory IBD. Further studies are warranted to better understand the role of the immune regulatory pathways in intestinal mucosa.

Long non-coding RNA Opa interacting protein 5-antisense RNA 1 binds to micorRNA-34a to upregulate oncogenic PD-L1 in non-small cell lung cancer

ABSTRACT Long non-coding RNA (lncRNA) OPA-interacting protein 5 antisense transcript 1 (OIP5-AS1) plays an oncogenic role in several types of cancer, but whether it is involved in non-small-cell lung cancer (NSCLC) is unclear. Our preliminary sequencing analysis revealed the upregulation of OIP5-AS1 in NSCLC. In this study, gene expression levels were analyzed by RT-qPCR. RNA-RNA pull-down assay was applied to detect direct interactions between RNAs. Overexpression assays were performed to explore the relationship between miR-34a and OIP5-AS1. CCK-8 assay and colony formation assay were applied to evaluate cell proliferation. In NSCLC cells (H23), overexpression of OIP5-AS1 increased the expression levels of programmed death-ligand 1 (PD-L1). In addition, inhibition of OIP5-AS1 and overexpression of miR-34a decreased the expression levels of PD-L1, and miR-34a significantly blocked the role of overexpression of OIP5-AS1. Overexpression of OIP5-AS1 and PD-L1 promoted H23 and H22 cells proliferation, while silencing of miR-34a and OIP5-AS1 played opposite roles and eliminated the effects of overexpression of OIP5-AS1 on cell proliferation. Therefore, OIP5-AS1 was upregulated to enhance the expression of oncogenic PD-L1 by sponging miR-34a in NSCLC, leading to promoted NSCLC cell proliferation. Our study also demonstrated that OIP5-AS1 was upregulated while miR-34a was downregulated in NSCLC.

MicroRNA-20a promotes non-small cell lung cancer proliferation by upregulating PD-L1 by targeting PTEN.

Non-small cell lung cancer (NSCLC) remains one of the most common malignant tumors worldwide. The aim of the present study was to investigate the possibility of microRNA-20a (miR-20a) as a biomarker and therapeutic target for the diagnosis and treatment of NSCLC. Bioinformatics prediction, together with functional validation, confirmed miR-20a bound to programmed death ligand-1 (PD-L1) 3′-untranslated region to upregulate PD-L1 expression. Both miR-20a and PD-L1 could promote the proliferation of NSCLC cells. The expression level of PD-L1 was controlled by PTEN; however, further upstream regulation of PD-L1 expression was largely unknown. The present study showed that miR-20a could not restore the inhibition of PD-L1 expression levels by PTEN. Knockdown of PTEN expression upregulated the expression level of PD-L1 and promoted the proliferation of NSCLC cells. PTEN negatively regulated the Wnt/β-catenin signaling pathway by inhibiting β-catenin and Cyclin D1. Interestingly, PTEN could reverse miR-20a-mediated proliferation of NSCLC cells and the inhibitory effect was similar to that of XAV-939. miR-20a promotes the proliferation of NSCLC cells by inhibiting the expression level of PTEN and upregulating the expression level of PD-L1. It is suggested that miR-20a could be used as a biomarker and therapeutic target for the treatment of NSCLC.

Exosomal CD73 from serum of patients with melanoma suppresses lymphocyte functions and is associated with therapy resistance to anti-PD-1 agents

BackgroundCD73 is an ectonucleotidase producing the immunosuppressor mediator adenosine. Elevated levels of circulating CD73 in patients with cancer have been associated with disease progression and poor response to immunotherapy. Immunosuppressive...

Research Progress of Anti-PD-1/PD-L1 Immunotherapy Related Mechanisms and Predictive Biomarkers in NSCLC.

Programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) is an important pair of immune checkpoints (IC), which play an essential role in the immune escaping process of tumors. Anti-PD-1/PD-L1 immunotherapy can block the suppression effect of the immune system produced by tumor cells through the PD-1/PD-L1 axis and restore the pernicious effect of the immune system on tumor cells. The specific mechanism of anti-PD-1/PD-L1 immunotherapy is closely related to PI3K (phosphatidylinositol 3-kinase)/AKT (AKT serine/threonine kinase 1), JNK (c-Jun N-terminal kinase), NF-kB (nuclear factor-kappa B subunit 1), and other complex signaling pathways. Patients receiving anti-PD-1/PD-L1 immunotherapy are prone to drug resistance. The mechanisms of drug resistance mainly include weakening recognition of tumor antigens by immune cells, inhibiting activation of immune cells, and promoting the production of suppressive immune cells and molecules. Anti-PD-1/PD-L1 immunotherapy plays a vital role in non-small cell lung cancer (NSCLC). It is essential to find better efficacy prediction-related biomarkers and screen patients suitable for immunotherapy. At present, common biomarkers related to predicting immune efficacy mainly include PD-L1 expression level in tumors, tumor mutation burden (TMB), microsatellite instability (MSI)/mismatch repair (MMR), mutations of driver gene, etc. However, the screening efficacy of each indicator is not ideal, and the combined application of multiple indicators is currently used. This article comprehensively reviews anti-PD-1/PD-L1 immunotherapy-related mechanisms, drug resistance-related mechanisms, and therapeutic efficacy-related predictive biomarkers.

Predicting programmed death-ligand 1 expression level in non-small cell lung cancer using a combination of peritumoral and intratumoral radiomic features on computed tomography

In this study, we investigated the possibility of predicting expression levels of programmed death-ligand 1 (PD-L1) using radiomic features of intratumoral and peritumoral tumors on computed tomography (CT) images. We retrospectively analyzed 161 patients with non-small cell lung cancer. We extracted radiomic features for intratumoral and peritumoral regions on CT images. The null importance, least absolute shrinkage, and selection operator model were used to select the optimized feature subset to build the prediction models for the PD-L1 expression level. LightGBM with five-fold cross-validation was used to construct the prediction model and evaluate the receiver operating characteristics. The corresponding area under the curve (AUC) was calculated for the training and testing cohorts. The proportion of ambiguously clustered pairs was calculated based on consensus clustering to evaluate the validity of the selected features. In addition, Radscore was calculated for the training and test cohorts. For expression level of PD-L1 above 1%, prediction models that included radiomic features from the intratumoral region and a combination of radiomic features from intratumoral and peritumoral regions yielded an AUC of 0.83 and 0.87 and 0.64 and 0.74 in the training and test cohorts, respectively. In contrast, the models above 50% prediction yielded an AUC of 0.80, 0.97, and 0.74, 0.83, respectively. The selected features were divided into two subgroups based on PD-L1 expression levels≥50% or≥1%. Radscore was statistically higher for subgroup one than subgroup two when radiomic features for intratumoral and peritumoral regions were combined. We constructed a predictive model for PD-L1 expression level using CT images. The model using a combination of intratumoral and peritumoral radiomic features had a higher accuracy than the model with only intratumoral radiomic features.

Immunoregulatory effects of glioma-associated stem cells on the glioblastoma peritumoral microenvironment: a differential PD-L1 expression from core to periphery?

Glioma-associated stem cells (GASCs) have been indicated as possible players in supporting growth and recurrence in glioblastoma. However, their role in modulating immune response in the peritumoral area has not yet been described. In this study, the authors aimed to investigate programmed death-ligand 1 (PD-L1) differential expression at the protein level in GASCs derived from different tumor areas (core, periphery, and surrounding healthy brain). Tumor tissue samples were collected from patients who underwent surgery for a histopathologically confirmed diagnosis of glioblastoma. Sampling sites were confirmed via neuronavigation and categorized on 5-aminolevulinic acid (5-ALA) fluorescence as bright (ALA+), pale (ALA PALE), or negative (ALA-), which corresponds to the tumor mass, infiltrated peritumoral area, and healthy brain, respectively, during surgery. GASCs were first isolated from the 3 regions and analyzed; then Western blot analysis was used to evaluate the level of PD-L1 expression in the GASCs. Overall, 7 patients were included in the study. For all patients, the mean values ± SD of PD-L1 expression in GASCs for ALA+, ALA PALE, and ALA- were 1.12 ± 1.14, 0.89 ± 0.63, and 0.57 ± 0.18, respectively. The differentially expressed values of PD-L1 in GASCs sampled from the 3 areas were found to be significant (p < 0.05) for 3 of the 7 patients: patient S470 (ALA+ vs ALA- and ALA PALE vs ALA-), patient S473 (ALA+ vs ALA PALE and ALA PALE vs ALA-), and patient S509 (ALA+ vs ALA-). This analysis showed, for the first time, that GASCs expressed a constitutive level of PD-L1 and that PD-L1 expression in GASCs was not uniform among patients or within the same patient. GASC analysis combined with 5-ALA-guided sampling (from core to periphery) made it possible to highlight the role of the tumor microenvironment at the infiltrating margin, which might cause clinical resistance, opening interesting perspectives for the future.

Heterogeneity of programmed death-ligand 1 expression and infiltrating lymphocytes in paired resected primary and metastatic non-small cell lung cancer

Metastatic tumors (MTs) may show different characteristics of the immune microenvironment from primary tumors (PTs) in non-small cell lung cancer (NSCLC). The heterogeneity of immune markers in metastatic NSCLC and its associated factors has not been well demonstrated. In this study, 64 surgically resected specimens of paired PTs and MTs were obtained from 28 patients with NSCLC. Multiplex immunofluorescence (mIF; panel including programmed death-ligand 1 (PD-L1), Cytokeratin, CD8, and CD68) was performed on whole sections. The heterogeneity of the immune contexture of PD-L1 expression, infiltrating lymphocytes, and immune-to-tumor cell distances was quantified via digital image analysis. In a quantitative comparison of MTs and corresponding PTs, MTs showed higher PD-L1 expression levels, lower density of CD8+ cytotoxic T lymphocytes (CTLs), and longer spatial distance between CTLs and tumor cells. Subgroup analysis, which associated clinical factors, revealed that the heterogeneity of immune markers was more obvious in extrapulmonary, metachronous, and treated MTs, while fewer differences were observed in intrapulmonary, synchronous, and untreated MTs. In particular, MTs showed significantly higher PD-L1 expression and lower lymphocyte infiltration in metastatic NSCLC with EGFR mutations. Prognosis analysis showed that an increased density of CD8+ CTLs in MTs was associated with better overall survival (OS). Therefore, significant discrepancies in PD-L1 expression and lymphocyte infiltration in metastatic NSCLC are most likely associated with temporal heterogeneity with a history of anti-treatment and correlated with EGFR mutations. The detection of immune markers in re-obtained metastatic specimens may be required for immunotherapy prediction in these patients with metastatic NSCLC.

Inhibition of interferon-gamma-stimulated melanoma progression by targeting neuronal nitric oxide synthase (nNOS)

Interferon-gamma (IFN-γ) is shown to stimulate melanoma development and progression. However, the underlying mechanism has not been completely defined. Our study aimed to determine the role of neuronal nitric oxide synthase (nNOS)-mediated signaling in IFN-γ-stimulated melanoma progression and the anti-melanoma effects of novel nNOS inhibitors. Our study shows that IFN-γ markedly induced the expression levels of nNOS in melanoma cells associated with increased intracellular nitric oxide (NO) levels. Co-treatment with novel nNOS inhibitors effectively alleviated IFN-γ-activated STAT1/3. Further, reverse phase protein array (RPPA) analysis demonstrated that IFN-γ induced the expression of HIF1α, c-Myc, and programmed death-ligand 1 (PD-L1), in contrast to IFN-α. Blocking the nNOS-mediated signaling pathway using nNOS-selective inhibitors was shown to effectively diminish IFN-γ-induced PD-L1 expression in melanoma cells. Using a human melanoma xenograft mouse model, the in vivo studies revealed that IFN-γ increased tumor growth compared to control, which was inhibited by the co-administration of nNOS inhibitor MAC-3-190. Another nNOS inhibitor, HH044, was shown to effectively inhibit in vivo tumor growth and was associated with reduced PD-L1 expression levels in melanoma xenografts. Our study demonstrates the important role of nNOS-mediated NO signaling in IFN-γ-stimulated melanoma progression. Targeting nNOS using highly selective small molecular inhibitors is a unique and effective strategy to improve melanoma treatment.

Comparative Analysis of Predictive Biomarkers for PD-1/PD-L1 Inhibitors in Cancers: Developments and Challenges.

Simple SummaryThe development of immune checkpoint inhibitors (ICIs) has greatly changed the treatment landscape of multiple malignancies. However, the wide administration of ICIs is mainly obstructed by the low response rate and several life-threatening adverse events. Thus, there is an urgent need to identify sets of biomarkers to predict which patients will respond to ICIs. In this review, we discuss the recently investigated molecular and clinical determinants of ICI response, from the aspects of tumor features, clinical features, as well as tumor microenvironment.Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) have dramatically changed the landscape of cancer therapy. Both remarkable and durable responses have been observed in patients with melanoma, non-small-cell lung cancer (NSCLC), and other malignancies. However, the PD-1/PD-L1 blockade has demonstrated meaningful clinical responses and benefits in only a subset of patients. In addition, several severe and life-threatening adverse events were observed in these patients. Therefore, the identification of predictive biomarkers is urgently needed to select patients who are more likely to benefit from ICI therapy. PD-L1 expression level is the most commonly used biomarker in clinical practice for PD-1/PD-L1 inhibitors. However, negative PD-L1 expression cannot reliably exclude a response to a PD-1/PD-L1 blockade. Other factors, such as tumor microenvironment and other tumor genomic signatures, appear to impact the response to ICIs. In this review, we examine emerging data for novel biomarkers that may have a predictive value for optimizing the benefit from anti-PD-1/PD-L1 immunotherapy.

Evaluation of PD-L1 Expression Level in Patients With Non-Small Cell Lung Cancer by 18F-FDG PET/CT Radiomics and Clinicopathological Characteristics.

PurposeIn the present study, we aimed to evaluate the expression of programmed death-ligand 1 (PD-L1) in patients with non-small cell lung cancer (NSCLC) by radiomic features of 18F-FDG PET/CT and clinicopathological characteristics.MethodsA total 255 NSCLC patients (training cohort: n = 170; validation cohort: n = 85) were retrospectively enrolled in the present study. A total of 80 radiomic features were extracted from pretreatment 18F-FDG PET/CT images. Clinicopathologic features were compared between the two cohorts. The least absolute shrinkage and selection operator (LASSO) regression was used to select the most useful prognostic features in the training cohort. Radiomics signature and clinicopathologic risk factors were incorporated to develop a prediction model by using multivariable logistic regression analysis. The receiver operating characteristic (ROC) curve was used to assess the prognostic factors.ResultsA total of 80 radiomic features were extracted in the training dataset. In the univariate analysis, the expression of PD-L1 in lung tumors was significantly correlated with the radiomic signature, histologic type, Ki-67, SUVmax, MTV, and TLG (p< 0.05, respectively). However, the expression of PD-L1 was not correlated with age, TNM stage, and history of smoking (p> 0.05). Moreover, the prediction model for PD-L1 expression level over 1% and 50% that combined the radiomic signature and clinicopathologic features resulted in an area under the curve (AUC) of 0.762 and 0.814, respectively.ConclusionsA prediction model based on PET/CT images and clinicopathological characteristics provided a novel strategy for clinicians to screen the NSCLC patients who could benefit from the anti-PD-L1 immunotherapy.

Correlation of epidermal growth factor receptor mutation status and PD-L1 expression with [18F]FDG PET using volume-based parameters in non-small cell lung cancer.

We investigated the relationship between 2-deoxy-2-[18F]fluoro-D-glucose (FDG) PET using volume-based parameters and epidermal growth factor receptor (EGFR) mutation status, programmed death-ligand-1 (PD-L1) expression level, and their combination, in pretreated non-small cell lung cancer (NSCLC). FDG PET findings and EGFR mutation status and PD-L1 expression level were investigated retrospectively in 93 patients with newly diagnosed NSCLC (77 adenocarcinomas, 16 squamous cell carcinomas). Tumors were divided into six groups: EGFR mutant/negative PD-L1, EGFR mutant/low PD-L1, EGFR mutant/high PD-L1, EGFR wild/negative PD-L1, EGFR wild/low PD-L1, and EGFR wild/high PD-L1. The maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) for primary tumor were measured from PET images. The EGFR mutation status and PD-L1 expression level were estimated in tumor tissue specimens and compared with the PET parameters. None of the PET parameters differed significantly between EGFR-mutated and wild-type EGFR. According to the PD-L1 level, significant differences were detected in SUVmax (P = 0.001) and TLG (P = 0.016), but not MTV. Comparing all six groups, significant difference was detected in only SUVmax (P = 0.011). Based on the preliminary results of this study, FDG PET may help in the prediction of PD-L1 expression level, but not EGFR mutation status, in patients with newly diagnosed NSCLC. The SUVmax rather than MTV or TLG, may be of value in predicting the six groups according to the combination of EGFR mutation status and PD-L1 expression level.

Cost-Effectiveness of Nivolumab Plus Ipilimumab With and Without Chemotherapy for Advanced Non-Small Cell Lung Cancer.

BackgroundFirst-line treatment with nivolumab plus ipilimumab (N+I) or nivolumab plus ipilimumab with two cycles of chemotherapy (N+I+chemotherapy) improve overall survival and progression-free survival for patients with metastatic non-small cell lung cancer (NSCLC), yet researchers have not concomitantly compared the cost-effectiveness of N+I and N+I+chemotherapy with chemotherapy alone.Materials and methodsUsing outcomes data from the CheckMate 227 and CheckMate 9LA phase 3 randomized trials, we developed a Markov model with lifetime horizon to compare the costs and effectiveness of N+I and N+I+chemotherapy versus chemotherapy from the U.S. health care sector perspective. Subgroup analysis by programmed death-ligand 1 (PD-L1) expression levels (≥1% and <1%) and probabilistic analysis were performed.ResultsThe incremental cost-effectiveness ratio (ICER) of N+I versus chemotherapy was $239,072 per QALY, and $838,198 per QALY for N+I+chemotherapy versus N+I. The ICER of N+I versus chemotherapy was $246,584 per QALY for patients with PD-L1 ≥ 1% and $185,620 per QALY for those with PD-L1 < 1%. In probabilistic analysis, N+I had a 2.6% probability of being cost-effective at a willingness-to-pay threshold of $150,000 per QALY. The probability was 0.4% for patients with PD-L1 ≥ 1% and 10.6% for patients with PD-L1 < 1%.ConclusionFirst-line N+I or N+I+chemotherapy for metastatic NSCLC was not cost-effective regardless of PD-L1 expression levels from the U.S. health care sector perspective.

Potential PD-L1 expressing cytotoxic T-cell immunopathology in Alzheimer disease.

Growing evidence suggested that adaptive immunity involved Alzheimer's disease (AD). Peripheral blood mononuclear cell (PBMC) subpopulations and expression of immune checkpoints such as programmed death-ligand 1(PD-L1) and programmed cell death protein-1 (PD-1) could play roles in Alzheimer disease. The interaction of PD-L1/PD-1 lead PD-1 expressing T cells to attenuate T cell-activating signals. Recent studies had demonstrated the blockade of PD-L1/PD-1 axis modified brain pathology and restored cognitive performance in tauopathy murine model. However similar human experiment suggested controversial results in AD patients. To observe the changes of PBMC subpopulations and PD-L1/PD-1 expression in AD and healthy controls, we utilized flow cytometry, and applied t-distributed stochastic neighbor embedding (t-SNE) algorithm as a new approach to analyze results. AD patients (n=16) with different disease severity (CDR= 1 - 2) and healthy controls (n=16) were enrolled. Expression levels of PD-L1/PD-1 in AD patients and healthy controls were derived by flow cytometric analysis parameters. Moreover, a dimensionality reduction algorithm for visualized t-SNE, was implemented to analyze the PD-L1/PD-1 expressing cell clusters between AD patients and healthy controls. We found no significant PD-1 expression intensity difference between cytotoxic T lymphocytes (CTL) of AD patients and healthy controls. In AD patients, subpopulation of CTL expressing PD-L1 was elevated by 85.53%. Further, PD-L1 expressing CTL clusters between AD patients and healthy controls were compared. We observed that densities of PD-L1high CTL clusters are significantly higher than the healthy controls. Upregulation of PD-L1 and PD-L1 expressing CTL were increased in peripheral blood of AD patients, linking to newly found strong correlation between the level of PD-L1 positive CTL and markers which indicated negative immune climate. Abnormal adaptive immune response of CTL might associate with concurrent viral infection, intracellular bacterial infection, and underlying cancer in AD patients. Our results suggested a novel strategy to prevent AD progression with regulation of PD-L1 expressing CTL, and notation of underlying intracellular infection and malignancy for which could relate to dementia progression.

Relationship of the lung microbiome with PD-L1 expression and immunotherapy response in lung cancer

BackgroundLung cancer is the primary cause of cancer-related deaths worldwide. The human lung serves as a niche to a unique and dynamic bacterial community that is related to the development of multiple diseases. Here, we investigated the differences in the lung microbiomes of patients with lung cancer.Methods16S rRNA sequencing was performed to evaluate the respiratory tract microbiome present in the bronchoalveolar lavage fluid. Patients were stratified based on programmed death-ligand 1 (PD-L1) expression levels and immunotherapy responses.ResultsIn total, 84 patients were prospectively analyzed, of which 59 showed low (< 10%), and 25 showed high (≥ 10%) PD-L1 expression levels. The alpha and beta diversities did not significantly differ between the two groups. Veillonella dispar was dominant in the high-PD-L1 group; the population of Neisseria was significantly higher in the low-PD-L1 group than in the high-PD-L1 group. In the immunotherapy responder group, V. dispar was dominant, while Haemophilus influenzae and Neisseria perflava were dominant in the non-responder group.ConclusionThe abundances of Neisseria and V. dispar differed significantly in relation to PD-L1 expression levels and immunotherapy responses.