Tumor Programmed Death Ligand 1 Expression Research Articles

The correlation between PD-L1 expression and metabolic parameters of 18FDG PET/CT and the prognostic value of PD-L1 in non-small cell lung cancer

ObjectivesIn the present study, we aimed to investigate the relationship between metabolic parameters of 18F-fluorodeoxyglucose positron emission computed tomography (18F-FDG PET/CT) and the expression of programmed death ligand-1 (PD-L1), as well as the prognostic value of PD-L1, in patients with surgically resected non-small-cell lung cancer (NSCLC). Materials and methodsA total of 169 NSCLC patients who received preoperative 18F-FDG PET were retrospectively enrolled in the present study. The correlation between PD-L1 and patient characteristics was evaluated. Based on the expression of PD-L1 and metabolic parameters, patients were classified into low-, medium-, or high-risk groups. ResultsThe maximum standardized uptake value (SUVmax) and total lesion glycolysis (TLG) were significantly higher in NSCLC patients with high PD-L1 expression compared with the low expression group (P < 0.001 for all). Multivariate analysis revealed that pleural invasion (P < 0.001) and SUVmax (P < 0.001) were independent predictors of PD-L1 expression. Survival analysis showed that tumor stage (P = 0.004) and pleural invasion (P = 0.007) were independent prognostic indicators of progression-free survival (PFS). Tumor stage (P = 0.001), TLG (P = 0.039), and PD-L1 expression (P = 0.001) were independent prognostic indicators of overall survival (OS). Patients of the high-risk group with high PD-L1 expression and high TLG had a poor prognosis compared with the low-risk group (P < 0.05) and medium-risk group (P < 0.05). ConclusionsIn NSCLC patients, the SUVmax of 18F-FDG PET/CT was a predictor of PD-L1 expression. The expression of PD-L1 and TLG were independent prognostic factors of OS. The risk stratification standard based on the PD-L1 expression and TLG provided valuable insights into the development of personalized treatment and follow-up.Registration number:ChiCTR2100051554.

Crosstalk Between Programmed Death Ligand 1, Ki-67 Labelling Index, and Tumor-Infiltrating Lymphocytes in Invasive Breast Cancer and Clinicopathological Correlations in a Tertiary Care Center in Western India.

Background & Objective:Breast cancer is the leading cancer among Indian women and accounts for about 25% of all cancer cases worldwide. The present study aimed to assess Programmed Death Ligand-1 (PD-L1) expression in tumoral cells and tumor-infiltrating lymphocytes (TILs) and evaluate their correlations with the Ki-67 labelling index in invasive breast carcinomas (IBC). Methods:This descriptive observational study was conducted during 2016-2018 and included all diagnosed cases of IBC. The relationships between PD-L1 expression, TILs, hormone receptors, Ki-67, and clinicopathological parameters were studied in IBC. Statistical analysis was performed by SPSS version 23.Results:Out of 114 evaluated cases, 33.33% (N=38) showed PD-L1+ expression in tumor cells and 47.37% (N=54) had PD-L1+ expression in TILs. A high Ki-67 index was observed in 96 cases. Moreover, 49 patients were estrogen receptor (ER)- and 65 were ER+. We observed that 22 of 49 ER- and 49 of 65 ER+ subjects showed PD-L1+ expression, respectively. Conclusion: Our results showed a significant relationship between PD-L1 expression in tumoral cells and TILs, as well as between Ki-67 and TILs. In addition, an inverse correlation was noted between PD-L1 expression and ER. The PD-L1 expression in tumors and TILs and correlation with high Ki-67 may prove the importance of PD-L1 in targeted chemotherapy. An inverse relationship between PD-L1 and ER expression in tumoral cells suggests scope for immunotherapy in ER- IBC. However, further research with more cases is required.

Negative Correlation Between 18F-RGD Uptake via PET and Tumoral PD-L1 Expression in Non-Small Cell Lung Cancer.

PurposeWe investigated the correlation of 18F-AlF-NOTAPRGD2 (18F-RGD) uptake during positron emission tomography (PET) with tumoral programmed death-ligand 1 (PD-L1) expression and explored its potential in immune checkpoint inhibitor treatment.MethodsForty-two mice were subcutaneously injected with CMT-167 lung carcinoma cells. A total of 30 mice with good growth tumor and good general condition were selected. 18F-RGD PET scanning was performed on days 0, 2, 4, 6, 9, and 11 with five mice per day. Immunohistochemistry (IHC) for PD-L1 was performed on each specimen obtained from tumors. Thirty patients with advanced non-small cell lung cancer (NSCLC) were scanned using 18F-RGD PET/CT, and Milliplex multifactor detection analyzed serum PD-1/PD-L1 expression of twenty-eight of them. Thirteen of them were analyzed immunohistochemically using core needle biopsy samples obtained from primary tumors.ResultsThirty mice were scanned by 18F-RGD PET/CT and analyzed for PD-L1 expression in tumor cells by IHC finally. Maximum standard uptake value (SUVmax) and mean SUV (SUVmean) were significantly lower in relatively-higher-PD-L1-expression tumors than in relatively-low-PD-L1-expression tumors (P < 0.05). In patients, the SUVmax was significantly negatively correlated with tumoral PD-L1 expression by IHC (P=0.014). SUVmean, peak SUV (SUVpeak), and gross tumor volume (GTV) were also negatively correlated with PD-L1, but without significance (P > 0.05). SUVmax, SUVmean, SUVpeak, and GTV were negatively correlated with serum PD-1 and PD-L1, but not significantly. According to the receiver operating characteristic curve analysis, significant correlations between SUVmax and tumoral PD-L1 expression in both mice and patients were present (P < 0.05).ConclusionHigher 18F-RGD uptake is correlated with depressed PD-L1 expression in tumor cells, and SUVmax is the best parameter to display tumoral expression of PD-L1. 18F-RGD PET may be useful for reflecting the immune status of NSCLC.

Tumor budding in gastric adenocarcinoma; reflections on tumor microenvironment and programmed death ligand 1 (PD-L1) expression

Introduction: The significance of tumor budding and programmed death ligand 1 (PD-L1) has not been established in gastric adenocarcinoma (GAC). Objectives: This study evaluated tumor budding and PD-L1 expression with regard to tumor microenvironment, clinicopathologic parameters, and overall survival in GAC. Patients and Methods: Totally, 102 GAC cases were assessed immunohistochemically. The associations of tumor budding and PD-L1 with clinicopathologic features, tumor-infiltrating lymphocytes (TILs), tumor stroma percentage (TSP), and overall survival were analyzed. Results: High tumor budding (42.2% of cases) was correlated with distal tumor location, large tumor size, Helicobacter pylori infection, poor differentiation (P = 0.0008, 0.033, 0.011, and 0.005, respectively), lymphovascular invasion, high tumor and nodal stages, and TSP (all P &lt; 0.0001). Tumor budding was highest in the low TILs/high TSP group. PD-L1 expression (43.1% of cases) was correlated with proximal location (p = 0.00021), poor differentiation (P = 0.036), N stage (P = 0.049), high TILs (P &lt; 0.0001), and low tumor budding (P = 0.002). PD-L1 expression was highest in the low tumor budding / high TILs category (P &lt; 0.0001). Cox regression showed that high tumor budding (hazard ratio [HR]: 15.282, P = 0.024, 95% confidence interval [CI]: 1.441–162.069) and positive PD-L1 (HR: 7.502, P = 0.015, 95% CI: 1.469–38.31) were independent prognostic factors for overall survival. Conclusion: Tumor budding is correlated with poor prognostic parameters, whereas PD-L1 expression is inversely correlated with tumor budding. Both are independent predictors of short overall survival. Anti-PD-L1 immunotherapy could be effective in GAC with nodal metastasis, especially cases with high TILs and low tumor budding.

Expression and Prognostic Value of B7 Family Immune Checkpoints in Pancreatic Neuroendocrine Tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare malignancies with heterogeneous clinical courses requiring novel prognosticators and therapies. B7 family molecules have an important role in various cancers; however, these have not been distinguished in PanNETs. To investigate the expression and clinical significance of programmed death ligand-1 (PD-L1), programmed death ligand-2 (PD-L2), B7 homolog 3 (B7-H3), B7 homolog 4 (B7-H4), and V-domain immunoglobulin suppressor of T-cell activation (VISTA) in 182 PanNETs (with a high proportion of functioning versus nonfunctioning PanNETs: 51% versus 49%). Molecules were immunostained by using tissue microarrays from 182 patients with grade 1/2 PanNETs. VISTA-positive microvessel density (VISTA+ MVD) was evaluated in 4 high-power fields (HPFs) (×200) and mean count was calculated; immune cells with 1% or greater VISTA staining were considered positive. PD-L1 tumoral expression was considered positive in samples with 5% or more membranous staining. Tumoral VISTA, stromal PD-L1, PD-L2, B7-H3, and B7-H4 expression were deemed positive if any staining was observed. VISTA+ MVD was high (≥10.8/HPF) in 45 patients (25%), while VISTA stained positively on immune and tumor cells in 121 (66%) and 0 patients, respectively. Positive PD-L1 tumoral and stromal expression was observed in 23 (13%) and 0 patients, with positive B7-H3 expression in 76 (42%) and 98 (54%) patients, respectively, in these cells; PD-L2 and B7-H4 were not detected. PD-L1 positivity rate was high in functioning PanNETs. Stromal B7-H3 and high VISTA+ MVD correlated with unfavorable clinicopathologic features. Moreover, high VISTA+ MVD was an independent predictor of shorter progression-free survival. VISTA may serve as a prognosticator and immunotherapeutic target for patients with pancreatic neuroendocrine tumor (PanNET).

High exosomal PD-L1 expression in relation to lymph node progression in metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone (abi) or enzalutamide (enza).

e17038 Background: Programmed death-ligand 1 (PD-L1) has been recently found in tumor-derived exosomes and associated with progressive disease (PD) ( Poggio, Cell 2019). In localized prostate cancer, PD-L1 tumor expression has been shown to be a biomarker for node-positive patients (pts) ( Petitprez, Eur Urol Focus 2019) but its role in mCRPC is largely unexplored. We aimed to determine the potential of PD-L1 exosomal expression to predict lymph nodal PD in mCRPC receiving abi or enza. Methods: In a biomarker prospective study (REC 2192/2013), exosomes were isolated from plasma samples collected before first-line therapy with abi/enza between December 2014 and October 2018. RNA was extracted for analysis of PD-L1 by digital droplet PCR ( Del Re, Prostate Cancer Prostatic Dis 2021). Results: In our cohort of 55 node-positive mCRPC pts (median age: 76 years, range 47-89), the amount of exosomal PD-L1 expression (pts dichotomized in “high” and “low” as below or above median PD-L1/ACTB ratio = 0.0052) was associated with radiographic response after the first 3 months abi/enza therapy [high PD-L1 vs low PD-L1: 8 (25.8%) vs 0 (0%) PD, 23 (74.2%) vs 18 (75%) stable disease, and 0 vs 6 (25%) partial/complete response] (p = 0.0009). We observed an overall median progression-free survival (PFS) of 14.3 months [95% confidence interval (CI) 8.6-not reached] shorter in high PD-L1 compared to low PD-L1 10.6 (6.5-23.4) vs not reached [hazard ratio (HR) 3.1 (95% CI 1.1-8.5), p = 0.023]. In multivariable analysis including exosomal PD-L1 and androgen receptor (AR) variant 7, AR copy number gain detected in plasma, neutrophil lymphocyte ratio (NLR), lactate dehydrogenase, exosomal PD-L1; AR-V7 and AR gain were independent predictors of nodal PFS (HR 5.8, 95% CI 1.4-24.2, p = 0.01, HR 3.2, 95% CI 1.1-9.2, p = 0.03 and HR 12.9, 95% CI 2.3-73.2, p = 0.004), whereas AR-V7, AR gain, NLR &gt; 3 were independent predictors of OS (HR 4.9, 95% CI 1.8-13.1, p = 0.001, HR 4.4, 95% CI 1.1-17, p = 0.02, and HR 3.2 95% CI 1.1-9.4, p = 0.03, respectively). Moreover, a trend of a worse OS was reported in high PD-L1 compared to low PD-L1 pts (HR 2.6, 95% CI 0.9-7.5, p = 0.07). Conclusions: In mCRPC pts treated with ARSI, exosomal PD-L1 expression may be considered as a predictive biomarker of lymph nodal response, playing a potential role in individualized disease monitoring and treatment combining between ARSI and immunotherapy. Larger evaluation of treatment decisions based on exosomal PD-L1 expression is now required.

Analysis of the contribution of macrophages to the overall tumor PD-L1 microenvironment using a screening multi-tumor tissue microarray and rapid multiplex fluorescence digital phenotyping approach.

2620 Background: Programmed death ligand-1 (PD-L1) contributes to immune suppression in the tumor microenvironment (TME) by interacting with programmed cell death-1 (PD-1) on infiltrating T lymphocytes leading to tumor immune escape. Application of omics technologies has shed light on the relevance of the TME for response to immunotherapies and development of novel treatment options. Here we have applied a multi-plex immunofluorescence/multi-tumor tissue microarray (TMA) approach to examine the immunobiology of different TMEs with respect to the contribution by tumor cells and macrophages to overall PD-L1 expression. Methods: A TMA comprising 11 tumor types and a total of 144 different donors, each represented by two cores [1mm; 1 from invasive margin (IM) and 1 from tumor center (TC)], was stained using Ultivue’s Immuno8 FixVUE panel (CD3, CD4, CD8, FOXP3, CD68, PD-1, PD-L1, pan-CK/SOX10). Whole slide images from two rounds of imaging (x20 magnification; four markers in each round) were aligned using Ultivue's UltiStacker software based on the nuclear counterstains from the two imaging rounds, to provide precise marker colocalization data. Cell phenotype data for each core was generated using Visiopharm software. Results: Overall PD-L1 positivity was greatest for NSCLC, SCLC, TNBC and gastric cancer ranging from approximately 600-1000 PD-L1+ cells/mm2/core, compared with CRC, breast, pancreatic, liver, and gastric esophageal junction (GOJ) cancers (approx. 50-300 PD-L1+ cells/mm2/core). Contribution by macrophages to overall PD-L1 expression (dual CD68+/PD-L1+) varied by tumor type representing 25-35% for NSCLC (SCC and ADC) and gastric cancer, whereas a converse pattern was apparent for SCLC, TNBC, breast (ER+ and Her2+) and pancreatic cancers where PD-L1+ macrophages accounted for a large proportion (approx. 60-85%) of overall tumor PD-L1 expression. Interestingly, as a proportion of total macrophage infiltration, approximately 65% of CD68+ macrophages were PD-L1+ for SCLC and TNBC, compared with less than 10% for pancreatic and liver cancer. Spatial analysis revealed PD-L1+ macrophage infiltration to be generally higher for IM versus TC, and the distribution between tumor (CK+) and stroma (CK-) remained similar despite exclusion of CD3+/CD8+ cytotoxic T cells from CK+ tumor regions for pancreatic and liver cancer. Conclusions: Taken together, these data illustrate the benefits of combining multiplexed immunofluorescence staining, with digital analysis of cell phenotypes within well characterized tumor samples to better understand the relative immunobiology of different TMEs. Here we demonstrate that the relative contribution of macrophages to the overall PD-L1 microenvironment varies between tumor types, which may help guide options for successful immunotherapy strategies.

Results for patients with muscle-invasive bladder cancer (MIBC) in the CheckMate 274 trial.

4585 Background: In the CheckMate 274 trial, disease-free survival (DFS) was significantly improved with nivolumab (NIVO) vs placebo (PBO) both in intent-to-treat (ITT) patients (pts) (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in pts with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). We report results for the subgroup of pts with bladder cancer, the most predominant type of urothelial carcinoma. Methods: CheckMate 274 is a phase 3, randomized, double-blind trial of adjuvant NIVO vs PBO in high-risk muscle-invasive urothelial carcinoma (bladder, ureter, renal pelvis) after radical resection. Pts were randomized 1:1 to NIVO 240 mg intravenously every 2 weeks or PBO for ≤ 1 year of adjuvant treatment and stratified by nodal status, prior neoadjuvant cisplatin, and tumor PD-L1 expression. Pts had radical resection ± neoadjuvant chemotherapy and were at high risk of recurrence on final pathologic staging. Primary endpoints were DFS in ITT pts and in pts with PD-L1 ≥ 1%. Non–urothelial tract recurrence-free survival (NUTRFS) was a secondary endpoint, and distant metastasis-free survival (DMFS) was an exploratory endpoint. This exploratory analysis focused on the subgroup of pts with muscle-invasive bladder cancer (MIBC) after radical resection. Results: Of 709 randomized pts in the trial, 560 had MIBC (NIVO, n = 279; PBO, n = 281). With a minimum follow-up of 11.0 months, a DFS benefit was observed with NIVO vs PBO in these pts, regardless of tumor PD-L1 expression (Table). DFS probability at 12 months in all MIBC pts was 66% with NIVO and 45% with PBO. DFS was improved with NIVO vs PBO across subgroups according to age, sex, ECOG performance status, nodal status, and PD-L1 expression status. Improvement in NUTRFS and DMFS with NIVO vs PBO was also observed (Table). Grade 3–4 treatment-related adverse events occurred in 17% and 6% of pts in the NIVO and PBO arms, respectively. Conclusions: Improvement in DFS was observed with NIVO over PBO in pts with MIBC after radical resection regardless of tumor PD-L1 expression. The DFS benefit was observed in all prespecified subgroups. These results further support adjuvant NIVO as a standard-of-care treatment for pts with high-risk MIBC after radical resection ± neoadjuvant cisplatin-based chemotherapy. Clinical trial information: NCT02632409. [Table: see text]

Immuno-PET imaging of PD-L1 expression in patient-derived lung cancer xenografts with [68Ga]Ga-NOTA-Nb109.

Accurate evaluation of programmed death-ligand 1 (PD-L1) expression levels in cancer patients may be useful in the identification of potential candidates for anti-programmed death-1/PD-L1 (anti-PD-1/PD-L1) immune checkpoint therapy to improve the response rate of immune checkpoint blockade therapy. This study evaluated the feasibility of the nanobody-based positron emission tomography (PET) tracer [68Ga]Ga-NOTA-Nb109 for immuno-PET imaging of PD-L1 in lung cancer patient-derived xenograft (PDX). We constructed 2 PDXs of lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC) and used them for immuno-PET imaging. A 2-hour dynamic PET scanning was performed on the samples and the in vivo biodistribution and metabolism of [68Ga]Ga-NOTA-Nb109 were investigated using region of interest (ROI) analysis. The ex vivo biodistribution of [68Ga]Ga-NOTA-Nb109 in the 2 PDXs was investigated by static PET scanning. In addition, tumor PD-L1 expression in the 2 PDXs was evaluated by autoradiography, western blot, and immunohistochemical (IHC) analysis. Noninvasive PET imaging showed that [68Ga]Ga-NOTA-Nb109 can accurately and sensitively assess the PD-L1 expression in non-small cell lung cancer (NSCLC) PDX models. The maximum [68Ga]Ga-NOTA-Nb109 uptake by the ADC PDX LU6424 and the SCC PDX LU6437 were 3.13%±0.35% and 2.60%±0.32% injected dose per milliliter of tissue volume (ID/mL), respectively, at 20 min post injection. In vivo and ex vivo biodistribution analysis showed that [68Ga]Ga-NOTA-Nb109 was rapidly cleared through renal excretion and an enhanced signal-to-noise ratio (SNR) was achieved. Ex vivo PD-L1 expression analysis showed good agreement with in vivo PET imaging results. This study demonstrated that [68Ga]Ga-NOTA-Nb109 could be applied with PET imaging to noninvasively and accurately monitor PD-L1 expression in vivo for screening patients who may be responsive to immunotherapy and to guide the development of appropriate treatment strategies for such patients.

A bioinformatics-based immune-related prognostic index for lung adenocarcinoma that predicts patient response to immunotherapy and common treatments

BackgroundThere is increasing evidence of the effectiveness of immune checkpoint blockade (ICB) therapy for the treatment of lung adenocarcinoma (LUAD). However, the benefits of ICB therapy vary among LUAD patients. Due to the research dimension, existing biomarkers, such as programmed death-ligand 1 (PD-L1) expression and tumor mutation burden (TMB), could not reflect the complex tumor environment, and had low prediction accuracy of ICB. Therefore, we aimed to uncover a prognostic biomarker that could also predict whether a patient would benefit from ICB therapy and other common treatments from multiple dimensions, so as to improve the prediction accuracy of pre-treatment patients.MethodsBased on the LUAD dataset retrieved from The Cancer Genome Atlas (TCGA) database, 50 immune-related hub genes were identified using weighted gene co-expression network analysis and univariate Cox regression analyses. An immune-related gene prognostic index (IRGPI) was constructed using a Cox proportional-hazards model based on 15 genes and validated using GSE72094 dataset. We tested its prognostic accuracy by Kaplan-Meier (K-M) survival curves of the two datasets and assessed its predictive power by comparing area under curve (AUC) of IRGPI with existing biomarkers. Subsequently, we analyzed the molecular and immune characteristics, and evaluated the benefits of ICB by PD-L1 expression and Tumor Immune Dysfunction and Exclusion (TIDE) analysis, predicted the inhibitory concentration 50 of common treatments drugs for two IRGPI score-related subgroups.ResultsPatients in the IRGPI-high subgroup had lower overall survival (OS) than patients in the IRGPI-low subgroup in K-M survival curve in two cohorts. And IRGPI has AUC values of 0.715, 0.724, and 0.743 in 1, 2, and 3 years, respectively. A higher tumor mutation burden and PD-L1 expression and the tumor microenvironment (TME) landscape demonstrated that IRGPI-high subgroup patients may respond better to ICB therapy. Genomics of Drug Sensitivity in Cancer (GDSC) analysis indicated that the IRGPI-high subgroup showed greater sensitivity to chemotherapy.ConclusionsIRGPI is a prospective biomarker for evaluating whether a patient will benefit from ICB therapy and other treatments, and distinguishing patients with different molecular and immune characteristics.

DENR controls JAK2 translation to induce PD-L1 expression for tumor immune evasion

RNA-binding proteins (RBPs) can recognize thousands of RNAs that help to maintain cell homeostasis, and RBP dysfunction is frequently observed in various cancers. However, whether specific RBPs are involved in tumor immune evasion by regulating programmed death ligand-1 (PD-L1) is unclear. Here, we perform targeted RBP CRISPR/Cas9 screening and identify density regulated re-initiation and release factor (DENR) as a PD-L1 regulator. DENR-depleted cancer cells exhibit reduced PD-L1 expression in vitro and in vivo. DENR depletion significantly suppresses tumor growth and enhances the tumor-killing activity of CD8+ T cells. Mechanistically, DENR antagonizes the translational repression of three consecutive upstream open reading frames (uORFs) upstream of Janus kinase 2 (Jak2); thus, DENR deficiency impairs JAK2 translation and the IFNγ-JAK-STAT signaling pathway, resulting in reduced PD-L1 expression in tumors. Overall, we discover an RBP DENR that could regulate PD-L1 expression for tumor immune evasion, and highlight the potential of DENR as a therapeutic target for immunotherapy.

Prognostic and Predictive Role of PD-L1 Expression in Stage III Non-small Cell Lung Cancer Treated With Definitive Chemoradiation and Adjuvant Durvalumab

It is unclear whether programmed death ligand 1 (PD-L1) expression is prognostic or predictive of immunotherapy benefit among patients with stage III non-small cell lung cancer (NSCLC) treated with definitive chemoradiation and adjuvant durvalumab. We determined pretreatment tumor PD-L1 expression for 312 patients with stage III NSCLC treated with definitive chemoradiation and at least 1 dose of adjuvant durvalumab between November 2017 and April 2021 across the national Veterans Health Administration. Progression-free survival (PFS) and overall survival (OS) in PD-L1 expression subgroups (<1%, 1%-49%, and 50%-100%) were compared with 994 patients with stage III NSCLC treated without adjuvant durvalumab from 2015 to 2016. PD-L1 expression was <1%, 1% to 49%, and 50% to 100% in 109 (34.9%), 96 (30.7%), and 107 (34.3%) patients, respectively. Increasing PD-L1 expression was associated with longer PFS (adjusted hazard ratio [aHR], 0.84 per 25% absolute increase in expression; 95% confidence interval [CI], 0.75-0.94; P=.003) and OS (aHR, 0.86 per 25% absolute increase in expression; 95% CI, 0.74-0.99; P=.036). Compared with the no-durvalumab group, PFS was longer for PD-L1 50% to 100% (aHR, 0.44; 95% CI, 0.32-0.60; P < .001) and PD-L1 1% to 49% (aHR, 0.64; 95% CI, 0.47-0.86; P=.003) but not PD-L1 <1% (aHR, 0.84; 95% CI, 0.64-1.10; P=.19). Similar results were found for OS, with no significant difference between the no-durvalumab group and PD-L1 <1% (aHR, 0.81; 95% CI, 0.58-1.13; P=.22). Increasing tumor PD-L1 expression is prognostic for PFS and OS among patients with stage III NSCLC treated with adjuvant durvalumab, and patients with PD-L1 expression <1% may have limited benefit from adjuvant durvalumab.

Upregulated LINC01088 facilitates malignant phenotypes and immune escape of colorectal cancer by regulating microRNAs/G3BP1/PD-L1 axis.

Long intergenic non-coding RNA LINC01088 is a newly discovered long non-coding RNA (lncRNA). Its biological function in colorectal cancer (CRC) remains unknown. Here, 36 paired CRC and para-cancerous tissues were collected. In vitro, fluorescence in situ hybridization (FISH) assay, qPCR, western blotting analysis and cellular functional experiments, RNA immunoprecipitation (RIP) assay and dual-luciferase reporter system analysis were performed. In vivo, xenograft tumor mouse models were generated. Besides, patient-derived intestinal organoid (PDO) was generated ex vivo. We found that LINC01088 was significantly upregulated in colorectal cancer tissues and CRC cell lines compared to adjacent normal tissues and colonic epithelial cells. High LINC01088 levels were correlated with adverse outcomes in patients with CRC. LINC01088 was mainly located in the cytoplasm. LINC01088 knockdown suppressed the proliferation, migration, invasion, and immune escape of colorectal cancer cells. Mechanistically, LINC01088 bound directly to miR-548b-5p and miR-548c-5p that were significantly upregulated Ras GTPase-activating protein-binding proteins 1 (G3BP1) and programmed death ligand 1 (PD-L1) expression, altering CRC cell phenotypes. In mouse xenograft models, LINC01088 knockdown restrained CRC tumor growth and lung metastasis. Furthermore, G3BP1 overexpression reversed LINC01088-knockdown-mediated inhibitory effects on tumor growth. Notably, LINC01088 knockdown downregulated PD-L1 expression, while G3BP1 overexpression restored PD-L1 expression in xenograft tumors. Besides, LINC01088 knockdown repressed CRC organoid growth ex vivo. Overall, these findings suggested that LINC01088 directly targeted miR-548b-5p and miR-548c-5p, promoting G3BP1 and PD-L1 expression, which facilitated colorectal cancer progression and immune escape.

A computed tomography-based radiomics signature for predicting expression of programmed death ligand 1 in head and neck squamous cell carcinoma.

Accurate prediction of the expression of programmed death ligand 1 (PD-L1) in head and neck squamous cell carcinoma (HNSCC) before immunotherapy is crucial. This study was performed to construct and validate a contrast-enhanced computed tomography (CECT)-based radiomics signature to predict the expression of PD-L1 in HNSCC. In total, 157 patients with confirmed HNSCC who underwent CECT scans and immunohistochemical examination of tumor PD-L1 expression were enrolled in this study. The patients were divided into a training set (n = 104; 62 PD-L1-positive and 42 PD-L1-negative) and an external validation set (n = 53; 34 PD-L1-positive and 19 PD-L1-negative). A radiomics signature was constructed from radiomics features extracted from the CECT images, and a radiomics score was calculated. Performance of the radiomics signature was assessed using receiver operating characteristics analysis. Nine features were finally selected to construct the radiomics signature. The performance of the radiomics signature to distinguish between a PD-L1-positive and PD-L1-negative status in both the training and validation sets was good, with an area under the receiver operating characteristics curve of 0.852 and 0.802 for the training and validation sets, respectively. A CECT-based radiomics signature was constructed to predict the expression of PD-L1 in HNSCC. This model showed favorable predictive efficacy and might be useful for identifying patients with HNSCC who can benefit from anti-PD-L1 immunotherapy. • Accurate prediction of the expression of PD-L1 in HNSCC before immunotherapy is crucial. • A CECT-based radiomics signature showed favorable predictive efficacy in estimation of the PD-L1 expression status in patients with HNSCC.

Computer-assisted three-dimensional quantitation of programmed death-ligand 1 in non-small cell lung cancer using tissue clearing technology

Immune checkpoint blockade therapy has revolutionized non-small cell lung cancer treatment. However, not all patients respond to this therapy. Assessing the tumor expression of immune checkpoint molecules, including programmed death-ligand 1 (PD-L1), is the current standard in predicting treatment response. However, the correlation between PD-L1 expression and anti-PD-1/PD-L1 treatment response is not perfect. This is partly caused by tumor heterogeneity and the common practice of assessing PD-L1 expression based on limited biopsy material. To overcome this problem, we developed a novel method that can make formalin-fixed, paraffin-embedded tissue translucent, allowing three-dimensional (3D) imaging. Our protocol can process tissues up to 150 μm in thickness, allowing anti-PD-L1 staining of the entire tissue and producing high resolution 3D images. Compared to a traditional 4 μm section, our 3D image provides 30 times more coverage of the specimen, assessing PD-L1 expression of approximately 10 times more cells. We further developed a computer-assisted PD-L1 quantitation method to analyze these images, and we found marked variation of PD-L1 expression in 3D. In 5 of 33 needle-biopsy-sized specimens (15.2%), the PD-L1 tumor proportion score (TPS) varied by greater than 10% at different depth levels. In 14 cases (42.4%), the TPS at different depth levels fell into different categories (< 1%, 1–49%, or ≥ 50%), which can potentially influence treatment decisions. Importantly, our technology permits recovery of the processed tissue for subsequent analysis, including histology examination, immunohistochemistry, and mutation analysis. In conclusion, our novel method has the potential to increase the accuracy of tumor PD-L1 expression assessment and enable precise deployment of cancer immunotherapy.

Expanding the immunotherapy roadmap for hepatocellular carcinoma.

In a recent Lancet Oncology article, Yau etal. report the CheckMate 459 trial results. This is the first phase III trial comparing the single-agent anti-programmed death protein 1 (PD-1) therapy nivolumab to the tyrosine kinase inhibitor sorafenib for treatment-naive patients with advanced hepatocellular carcinoma.

Analysis of disease-free survival in CheckMate 274 by PD-L1 combined positive score and tumor proportion score.

491 Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P &lt; 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P &lt; 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS &lt; 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS &lt; 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS &lt; 1 (NIVO, n = 34; PBO, n = 38). Within TPS &lt; 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS &lt; 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS &lt; 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS &lt; 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients

BackgroundNivolumab plus ipilimumab demonstrated clinically meaningful improvement in efficacy versus chemotherapy with a manageable safety profile in patients with advanced non-small cell lung cancer (NSCLC) and tumor programmed death-ligand 1 (PD-L1) expression ≥1% or <1% in Part 1 of CheckMate 227. Here we report efficacy and safety results for the Asian subpopulation.MethodsPatients with stage IV/recurrent NSCLC were randomized 1 : 1 : 1 to nivolumab plus ipilimumab, nivolumab monotherapy, or chemotherapy (PD-L1 ≥1%) or nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Overall survival (OS), progression-free survival, objective response rate, duration of response, and safety were evaluated among patients in Japan, South Korea, and Taiwan.ResultsIn the Asian subpopulation with PD-L1 ≥1%, 81 patients received nivolumab plus ipilimumab and 81 received chemotherapy. Median OS was not reached with nivolumab plus ipilimumab versus 24.8 months with chemotherapy; 3-year OS rate was 53% versus 37% [hazard ratio (HR), 0.72; 95% confidence interval (CI) 0.47-1.11]. The 3-year progression-free survival rate was 26% versus 7% (HR, 0.65; 95% CI 0.45-0.96), objective response rate was 56% versus 37%, and median duration of response was 29.0 months (95% CI 15.0 months-not reached) versus 6.9 months (95% CI 3.9-11.1 months). Similar results were observed regardless of tumor PD-L1 expression and in Japanese patients. Grade 3-4 treatment-related adverse events occurred in 40% of patients receiving nivolumab plus ipilimumab and 36% receiving chemotherapy, in the overall Asian subpopulation (tumor PD-L1 expression ≥1% and <1%); no new safety signals were identified.ConclusionsAt 3-year follow-up, nivolumab plus ipilimumab provided durable long-term efficacy benefits versus chemotherapy regardless of tumor PD-L1 expression in the Asian subpopulation, including Japanese patients. Consistent with findings for all randomized patients, these data support the use of nivolumab plus ipilimumab as first-line treatment of Asian patients with advanced NSCLC.

Combined Association of Tumoral PD-L1 Expression and Pretreatment Presence of Epstein-Barr Virus DNA With Risk Stratification and Prognosis of Patients With Nasopharyngeal Carcinoma.

BackgroundLittle is known about whether the combination of tumor programmed death-ligand 1 (PD-L1) expression and pretreatment EBV DNA status can help stratify nasopharyngeal carcinoma (NPC) patients by risk of metastasis or predict prognosis.MethodsPD-L1 expression was assessed using immunohistochemical staining of 78 non-keratinizing NPC patients with clinical data. Survival outcomes and independent prognostic factors were identified.ResultsSeventy-eight patients were included, high PD-L1 expression was observed in 25 of 43 patients (58%) with metastasis, while it was observed only in 7 of 35 patients (20%) without metastasis. Multivariate analyses showed that progression-free survival (PFS) was independently predicted by tumoral PD-L1 expression and pretreatment EBV DNA status. When combining, 93.75% patients with high PD-L1 and EBV infection developed distant metastasis, and those patients were associated with worse PFS.ConclusionsBoth PD-L1 expression and pretreatment EBV DNA are closely related to metastasis and prognosis of NPC patients. Their combination can facilitate risk stratification and prognosis prediction, which may improve disease treatment and management.

The Role of Programmed Cell Death Receptor 1 in Lung Cancer.

Lung cancer is the most common cancer worldwide. Cancer immunotherapy is the activation of the immune system against cancer. The latest method of immunotherapy involves immune checkpoint inhibitors. Increased levels of programmed death ligand 1 (PD-L1) expression were observed on non-small-cell lung cancer. The association between PD-L1 expression and clinicopathological characteristics in lung cancer is still unclear. This is a cross-sectional, observational study that evaluated a sample of 41 lung cancer patients diagnosed between March 2019 and December 2020. PD-L1 tumor expression is described as a percentage. Patients were diagnosed with non-microcellular lung cancer and aged 37 to 87 years. Most patients were diagnosed with adenocarcinoma. According to the analysis, the average age of patients with negative PD-L1 tumors was 65.6 years, and of those with positive PD-L1 tumors was 63.6 years. The average value of the tumor proportion score for males was 26.97%, and for females 25.55%. No correlation was found between PD-L1 tumor expression and the age and sex of patients.