High Programmed Death-ligand 1 Expression Research Articles

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype.

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Quantitative Radiological Features and Deep Learning for the Non-Invasive Evaluation of Programmed Death Ligand 1 Expression Levels in Gastric Cancer Patients: A Digital Biopsy Study

Programmed Death-Ligand 1 (PD-L1) is an important biomarker for patient selection of immunotherapy in gastric cancer (GC). This study aimed to construct and validate a non-invasive virtual biopsy system based on radiological features and clinical factors to predict the PD-L1 expression level in GC. 217 patients who received gastrectomy for GC were consecutively enrolled in this study, with 157 patients from center 1 as the training cohort and 60 patients from center 2 as the external validation cohort. 1205 quantitative radiomics features were extracted from preprocessed pre-operative contrast-enhanced CT images of enrolled patients. A radiological signature was computed using a regression random forest model and was integrated with clinical factors in a multilayer perceptron. The performance of the digital biopsy system was evaluated by the receiver operating characteristic (ROC) curve and calibration curve in both the training and validation cohort. 15 features were selected for the construction of radiological signature, which was significantly associated with expression levels of PD-L1 in both the training cohort (p<0.0001) and the external validation cohort (p<0.01). The hybrid deep learning model integrating the radiological signature and clinical factor could accurately distinguish GCs with high PD-L1 expression levels in both the training cohort (AUC = 0.806, 95%CI: 0.736-0.875) and the validation cohort (AUC = 0.784, 95%CI: 0.668-0.901). Our results indicate that the combination of deep learning and quantitative radiological features are potential approaches for the non-invasive evaluation of PD-L1 expression levels in GC. The digital biopsy system could provide valuable suggestive information for clinical decision-making of immunotherapy in GC.

Distribution and concordance of PD-L1 expression by routine 22C3 assays in East-Asian patients with non-small cell lung cancer

BackgroundCurrently, programmed death ligand-1 (PD-L1) expression has been widely applied in clinical trials and real-world clinical practice as a major biomarker for the efficacy of immune-checkpoint inhibitors. The purpose of this study is to reveal the distribution and concordance of PD-L1 expression in a large-scale consecutive cohort from East-Asian patients with non-small cell lung cancer (NSCLC).MethodsPD-L1 testing was conducted using 22C3 assays, and cases were categorized into the high, low, and no expression of PD-L1 based on the tumor proportion score (TPS). Target-capture next-generation sequencing was used to identify molecular events.ResultsA total of 4550 patients and 4622 tests of PD-L1 expression were enrolled. There were 3017 (66.3%) patients with no PD-L1 expression (TPS < 1%), 1013 (22.3%) with low PD-L1 expression (TPS 1–49%), 520 (11.4%) with high PD-L1 expression (TPS ≥ 50%). Higher proportions of positive PD-L1 expression (TPS ≥ 1%) were observed in smokers, males, squamous cell carcinoma, and high-grade lung adenocarcinoma. Further analyses revealed fair agreement in primary and metastatic lesions (kappa = 0.533), poor agreement in multi-focal primary tumors (kappa = 0.045), and good agreement in biopsy and resection samples (kappa = 0.662) / two biopsy samples (kappa = 0.711). Mutational analyses revealed association between high PD-L1 expression (TPS ≥ 50%) and EGFR wild-type, KRAS mutation, ALK rearrangement, and TP53 mutation.ConclusionThe study reveals the unique distribution pattern of PD-L1 expression in a large-scale East-Asian cohort with NSCLC, the concordance of multiple PD-L1 tests, and the association between PD-L1 expression and molecular events. The results shed a light on the optimization of PD-L1 testing in clinical practice.

PD-L1 Expression in High-Risk Early-Stage Colorectal Cancer-Its Clinical and Biological Significance in Immune Microenvironment.

Programmed death-ligand 1 (PD-L1) is an immune checkpoint molecule that can regulate immune responses in the tumor microenvironment (TME); however, the clinical applications of PD-L1 in early-stage colorectal cancer (CRC) remain unclear. In this study, we aimed to investigate the relationship between PD-L1 expression and survival outcome and explore its relevant immune responses in CRC. PD-L1 expression was evaluated by immunohistochemical staining to determine the tumor proportion score and combined positive score (CPS) in a Taiwanese CRC cohort. The oncomine immune response research assay was conducted for immune gene expression analyses. CRC datasets from the TCGA database were reappraised for PD-L1-associated gene enrichment analyses using GSEA. The high expression of PD-L1 (CPS ≥ 5) was associated with longer recurrence-free survival (p = 0.031) and was an independent prognostic factor as revealed by multivariate analysis. High PD-L1 expression was related to six immune-related gene signatures, and CXCL9 is the most significant overexpressed gene in differential analyses. High CXCL9 expression correlated with increased infiltration levels of immune cells in the TME, including CD8+ T lymphocytes and M1 macrophages. These findings suggest that high PD-L1 expression is a prognostic factor of early-stage CRC, and CXCL9 may play a key role in regulating PD-L1 expression.

Modifying factors of PD-L1 expression on tumor cells in advanced non-small-cell lung cancer.

Programmed death ligand-1 (PD-L1) expression predicts immunotherapy utility in nononcogenic addictive lung adenocarcinoma (ADC). However, its reproducibility and reliability may be compromised outside clinical trials. This study aimed to evaluate factors associated with PD-L1 expression in lung ADC. This observational study assessed 547 tumor samples with advanced lung ADC from January 2016 to December 2020 in a single cancer institution. Tumor samples were stained by at least one approved PD-L1 clone, SP263 (Ventana) or 22C3 (Dako), and stratified in tumor proportion score (TPS) <1%, 1-49%, or ≥50%. Of all the tumor samples, positive PD-L1 staining was higher in poorly differentiated tumors (67.3% vs. 32.7%, p < 0.001). Analytical factors associated with a PD-L1 high expression (TPS ≥ 50%) were the SP263 clone (19.6% vs. 8.2%, p < 0.001), time of archival tumor tissue <12 months (15.3% vs. 3.8%, p=0.024), whenever the analysis was performed in the most recent years (2019-2020) (19.0% vs. 8.3%, p < 0.001), and whenever the analysis was performed by pathologists in the academic setting (Instituto Nacional de Cancerologia, INCan) (19.9% vs. 11.9%, p=0.001). In the molecular analysis, EGFR wild-type tumors had an increased proportion of PD-L1 positive and PD-L1 high cases (60.2% vs. 47.9%, p=0.006 and 17.4% vs.8.5%, p=0.004). A moderate correlation (r=0.69) in the PD-L1 TPS% was observed between the two different settings (INCan vs. external laboratories). Clinicopathological factors were associated with an increased PD-L1 positivity rate. These differences were significant in the PD-L1 high group and associated with the academic setting, the SPS263 clone, time of archival tumor tissue <12 months, and a more recent period in the PD-L1 analysis.

Programmed death-ligand 1 (PD-L1) expression in Hodgkin’s lymphoma among Peruvian patients

Objective: Various studies on Hodgkin’s lymphoma (HL) have determined programmed death-ligand 1 (PD-L1) expression in Hodgkin and Reed-Sternberg (HRS) cells, with variable results. This protein has gained relevance for its role in theimmune response in malignant neoplasms. This work aimed to determine PD-L1 immunohistochemical expression in HRS cells and its relationship with age, sex, clinical stage and overall survival (OS) in a cohort of Peruvian patients. Materials and methods: Twenty-five (25) biopsies from patients diagnosed with HL were assessed, which allowed determining PD-L1 immunohistochemical expression in HRS cells in relation to OS and clinical data of the patients. Results: All cases showed PD-L1 expression in more than 1 % of tumor cells. There was no statistically significant difference in OS when two groups were compared in terms of PD-L1 expression with a cut-off point of 50 %, clinical stage (CS), age and sex. Conclusions: High PD-L1 expression was found in pre-treatment HL tumors. No association was found between PD-L1 expression, OS, age, sex or CS. Further studies with a larger number of patients are necessary to reassess the prognosticimpact of the expression of this protein in HL.

Pembrolizumab vs cemiplimab for the treatment of advanced non-small cell lung cancer with PD-L1 expression levels of at least 50%: A network meta-analysis and cost-effectiveness analysis.

BackgroundPembrolizumab and cemiplimab have been approved as treatment for advanced non-small-cell lung cancer (NSCLC) with high programmed death ligand-1 (PD-L1) expression. This study aimed to evaluate the cost-effectiveness of pembrolizumab compared with that of cemiplimab in the treatment of advanced NSCLC with high PD-L1 expression from a societal perspective in the United States.Materials and methodsCost-effectiveness analysis integration of the network meta-analysis framework was performed using data from the EMPOWER-Lung 1, KEYNOTE 024, and KEYNOTE 042 phase 3 randomized clinical trials. A network meta-analysis including 2289 patients was constructed, and the Markov and partitioned survival (PS) models were used to assess the cost-effectiveness of pembrolizumab compared with that of cemiplimab for the treatment of high PD-L1 expression (≥50% of tumor cells). The time horizon was 10 years. The main outcomes were overall costs, incremental cost-effectiveness ratios (ICERs), quality-adjusted life-years (QALYs), life-years, incremental net health benefits (INHB), and incremental net monetary benefits (INMB). The robustness of the model was verified using one-way and probabilistic sensitivity analyses, and subgroup analyses were conducted.ResultsTreatment of advanced NSCLC with high PD-L1 expression with pembrolizumab achieved 0.093 QALYs and was associated with an incremental cost of $10,657 compared with cemiplimab, yielding an ICER of $114,246/QALY. The ICER in the PS model was similar to that in the Markov model, with a difference of $3,093/QALY. At a willingness-to-pay (WTP) threshold of $100,000/QALY, INHB, and INMB of pembrolizumab were -0.013 QALYs and -$1,329, respectively, and the probability of cemiplimab was 51% when compared with pembrolizumab. When the WTP threshold increased to $150,000/QALY, the INHB and INMB of pembrolizumab were 0.022 QALYs and $3,335, respectively, and the probability of pembrolizumab was 51.85%. One-way sensitivity analysis indicated that the models were sensitive to pembrolizumab and cemiplimab costs. Subgroup analysis revealed that treatment with pembrolizumab was related to a higher INHB in several subgroups, including patients with brain metastases at baseline.ConclusionOur findings suggest that the WTP threshold should be considered when choosing between cemiplimab and pembrolizumab to treat advanced NSCLC with high PD-L1 expression. Reducing the cost of pembrolizumab may lead to valuable outcomes.

Comparison of the tumor immune microenvironment phenotypes in different breast cancers after neoadjuvant therapy.

Neoadjuvant therapy (NAT) treats early-stage breast cancers, especially triple-negative breast cancers (TNBCs). NAT improves pathological complete response (pCR) rates for different breast cancer patients. Recently, immune checkpoint inhibitors that target programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1) in combination with NAT have shown antitumor activity in patients with early breast cancer. However, the tumor immune microenvironment (TME) in different subtypes of breast cancers, like TNBC, hormone receptor-positive (HR+), and human epidermal growth factor receptor 2 amplified (HER2+) and its changes by NAT remain to be fully characterized. We analyzed pre-NAT tumor biopsies from TNBC (n=27), HR+ (n=24), and HER2+ (n=30) breast cancer patients who received NAT, followed by surgery. The different immune makers (PD-1, PD-L1, CD3, and CD8) of tumor-infiltrating lymphocytes (TILs) were identified with immunofluorescence-based microenvironment analysis. TILs within cancer parenchyma (iTILs) and in cancer stroma (sTILs) were counted separately. We found that PD-L1+ cells in tumor and stroma were significantly higher in TNBC patients than in others. PD-L1+ sTILs were significantly higher in pCR than in non-pCR patients of all the subtypes. The infiltration scores of B-cell memory, T-cell CD4+ memory activated, T-cell follicular helper, and Macrophage M0 and M1 were relatively higher in TNBC patients, indicating immunoreactive TME in TNBC. Analysis of TCGA-BRCA RNA-seq indicated that PD-L1 was highly expressed in TNBC patients compared with HR+ and HER2+ patients. Higher PD-L1 expression in TNBC patients was associated with significantly longer overall survival (OS). Our results demonstrated that PD-L1 expression level of iTILs and sTILs is highest in TNBC among breast cancers. TNBC patients had significantly different immunoreactive TME compared with HR+ and HER2+ patients, suggesting potentially favorable outcomes for immunotherapy in these patients. Also, PD-L1+ could be a powerful predictor of pCR in TNBC patients after NAT.

Impact of gender on response to immune checkpoint inhibitors in patients with non-small cell lung cancer undergoing second- or later-line treatment.

BackgroundSeveral previous clinical trials have reported that male patients with non-small cell lung cancer (NSCLC) respond better to immunotherapy than females. However, the impact of gender on prognosis remains uncertain because no real-world study considering various factors that affect patients’ response to immunotherapy with gender exists. Therefore, we evaluated the effect of gender on immunotherapy response adjusted by multiple factors in actual clinical practice.MethodsThis study was a single-center real-world retrospective cohort study, comprising 387 patients with NSCLC who received pembrolizumab, nivolumab, or atezolizumab alone as second- or later-line treatments. Subsequently, we compared their progression free survival (PFS) and overall survival (OS) scores based on gender, then analyzed prognostic factors accounting for immunotherapy response.ResultsThe mean age of the understudied patients was 64.0 years old, comprising 68.7% males, with non-squamous cell carcinoma accounting for 70.3% of these patients. Male patients also showed higher smoking rates, programmed death-ligand 1 (PD-L1) expression, and expression of wild type epidermal growth factor receptor (EGFR), known as favorable prognostic factors. However, no difference in PFS and OS according to gender was observed [PFS 2.2 (male) vs. 2.1 (female) months, P=0.144; OS 7.6 (male) vs. 8.8 (female) months, P=0.383]. Furthermore, an Eastern Cooperative Oncology Group (ECOG) performance status ≥2, high expression of PD-L1, and EGFR mutations were proposed as prognostic factors in multivariate analysis for PFS. Besides, ECOG performance status ≥2 and squamous cell carcinoma were poor prognostic factors accounting for OS. Yet, gender was not an independent prognostic factor in PFS and OS.ConclusionsGender was not an independent prognostic factor for immunotherapy in real-world data although various factors affected immunotherapy response, such as wild type EGFR and high expression of PD-L1, which frequently occur in males.

1775P Prevalence of PD-L1 high expression in advanced urothelial carcinoma (aUC): Results from the PREVAIL prospective cohort study

Programmed death-ligand 1 (PD-L1) expression in aUC has been studied extensively in clinical trials. In the DANUBE trial, 60% of patients (pts) with aUC had high tumor PD-L1 expression using the Ventana PD-L1 (SP263) Assay. As the first-line (1L) aUC therapy landscape keeps evolving, discovery and validation of biomarkers with the clinical utility to enable patient selection is important. In that context, there is a need to better understand testing practices and the prevalence of PD-L1 for patients with aUC in the real-world setting.

Immunotherapy-chemotherapy combinations for non-small cell lung cancer: current trends and future perspectives

ABSTRACT Introduction In recent years, immunotherapy has become a pillar in the treatment of advanced, non-oncogene-addicted non-small cell lung cancer (NSCLC). Programmed death ligand 1 (PD-L1) expression is currently the only factor used to predict response to immunotherapy in clinical practice. Specifically, single-agent pembrolizumab as first-line therapy is approved for tumors with high expression of PD-L1 (≥50%) while immunotherapy and chemotherapy are approved for any PD-L1. However, combinations of immune-checkpoint inhibitors (ICIs) and other agents may confer higher benefit than immunotherapy alone in some circumstances. Areas covered We reviewed the available data regarding the combined use of ICIs and chemotherapy in patients with advanced, treatment-naïve NSCLC. In light of the benefit demonstrated in advanced disease, these combinations have been subsequently tested in other settings. We collected the most relevant findings regarding efficacy and safety of chemo-immunotherapy combinations in early and locally advanced NSCLC. Expert opinion Immune-chemotherapy combinations demonstrated benefit in the advanced setting, and this strategy in now being applied in the early and local advanced settings. A description of clinical and biological predictors of response is required in order to identify patients who may benefit the most from combination therapy.

Regulation of PD-L1 through direct binding of cholesterol to CRAC motifs.

Cholesterol, an essential molecule for cell structure, function, and viability, plays crucial roles in the development, progression, and survival of cancer cells. Earlier studies have shown that cholesterol-lowering drugs can inhibit the high expression of programmed-death ligand 1 (PD-L1) that contributes to immunoevasion in cancer cells. However, the regulatory mechanism of cell surface PD-L1 abundance by cholesterol is still controversial. Here, using nuclear magnetic resonance and biochemical techniques, we demonstrated that cholesterol can directly bind to the transmembrane domain of PD-L1 through two cholesterol-recognition amino acid consensus (CRAC) motifs, forming a sandwich-like architecture and stabilizing PD-L1 to prevent downstream degradation. Mutations at key binding residues prohibit PD-L1–cholesterol interactions, decreasing the cellular abundance of PD-L1. Our results reveal a unique regulatory mechanism that controls the stability of PD-L1 in cancer cells, providing an alternative method to overcome PD-L1–mediated immunoevasion in cancers.

Predictive values of PD‑L1 expression for survival outcomes in patients with cervical cancer: a systematic review and meta-analysis.

Cervical cancer is one of the most common cancers in women worldwide. Although mortality has declined over the past 30 years in high-income areas, it remains a problem in several countries. Given that the prognosis of patients with recurrent or metastatic disease is poor, it is necessary to identify valuable predictive indicators to estimate survival outcomes in patients with cervical cancer. We searched electronic databases such as PubMed, Web of Science, Embase, Ovid MEDLINE, and the Cochrane Central Register of Controlled Trials, and investigated the relationship between Programmed death-ligand 1(PD-L1) expression and prognosis. Chi squared tests and I2 were utilized to assess study heterogeneity, and publication bias was estimated using Begg's funnel plot and Egger linear regression test. Thirteen eligible studies with 1422 patients were included. Generally, high PD-L1 expression was conclusively associated with poor overall survival (OS) (HR: 1.31; 95% CI 1.03-1.66, p = 0.025). However, PD-L1 expression demonstrated no association with progression-free survival (HR: 0.93; 0.73-1.19, p = 0.57). High PD-L1 expression with a sample size over 100 indicated a shorter OS (HR: 1.51; 95% CI 1.13-2.01). High expression of PD-L1 in Asians represented a lower OS (HR: 1.52; 1.14-2.03). Overexpression of PD-L1 in tumor cells (HR: 1.57; 1.29-2.10) and tumor-infiltrating immune cells (HR: 1.75; 1.02-2.99) predicted poor OS. High PD-L1 expression (HR: 4.04; 2.58-6.31) showed a lower effect on OS with a cut-off value of 5%. Our results indicate that high PD-L1 expression could be a valuable biomarker for predicting clinical outcomes in patients with cervical cancer.

Colon metastasis from lung adenocarcinoma with BRAF V600E mutation: A case report

Symptomatic colon metastasis from primary lung cancer is rare in clinical practice. We report the case of a 58-year-old patient with advanced lung adenocarcinoma who developed abdominal symptoms, including abdominal distention and difficulty defecating, after immunotherapy and chemotherapy. The patient was diagnosed with lung adenocarcinoma, and systemic positron emission tomography-computed tomography confirmed multiple lymph node, pleural, and adrenal metastases. Molecular detection indicated BRAF V600E mutation and high programmed death-ligand 1 (PD-L1) expression. After first-line anti-programmed cell death protein 1 immunotherapy combined with chemotherapy, the nodes in the chest remarkably diminished. However, it was followed by colon obstruction, incomplete ileus, and bone metastasis. Endoscopic histological examination confirmed adenocarcinoma but could not identify primary or secondary tumors due to insufficient tissue. We performed colon resection to remove the obstruction, and postoperative tissue pathological microscopy confirmed metastasis from the lung adenocarcinoma. We corroborated the BRAF V600E mutation and high PD-L1 expression and supported the molecular features of lung adenocarcinoma. During hospitalization, the patient presented with unbearable pain in the bone metastases, and palliative radiotherapy was administered. Then, the patient received dabrafenib plus trametinib as the second-line therapy. This report discusses the clinical characteristics, pathology, imaging, molecular profile assessments, and treatment of primary lung adenocarcinoma with colon metastasis.

A retrospective study for prognostic significance of type II diabetes mellitus and hemoglobin A1c levels in non-small cell lung cancer patients treated with pembrolizumab

BackgroundDiabetes mellitus (DM) is common and recognized as a risk factor for developing non-small cell lung cancer (NSCLC) while the prognostic evaluation is still controversial. As immunotherapy is widely used in clinical practice, its efficacy and survival should be investigated in patients with DM.MethodsWe retrospectively recruited 266 locally advanced and metastatic NSCLC patients who received pembrolizumab alone or in combination with chemotherapy. Patients’ clinicopathological data, including age, history of DM, hemoglobin A1c (HbA1c), genetic tumor profiling, and survival data were collected. Associations between clinical characteristics and survival were evaluated by univariate and multivariate analyses.ResultsIn this cohort, 15.04% (40/266) of the patients had a history of DM. Fifty-nine (22.2%) patients had a HbA1c level ≥6.5%. A total of 169 (63.5%) patients received 1st-line therapy, and 97 (36.5%) received 2nd- or subsequent-line therapy. Patients with high (≥6.5%) HbA1c and lower (<35 g/L) albumin levels at baseline had worse survivals, and epidermal growth factor receptor (EGFR) mutants significantly associated with worse outcomes at normal HbA1c (<6.5%) levels (all P<0.05). Among the 1st-line therapy patients, a higher HbA1c level (≥6.5%) at baseline indicated a worse overall survival (OS) (2-year survival rate: 31.25% vs. 27.03%, P=0.045), tumor protein p53 (TP53) alternations and high programmed death-ligand 1 (PD-L1) expression (≥50%) were significantly associated with better outcomes (P<0.05). For 2nd- or subsequent-line patients, EGFR mutants and non-squamous carcinomas (non-SCs) indicated worse survivals, and the normal peripheral blood markers of the carcinoembryonic antigen (CEA), C-reactive protein (CRP), albumin levels were favorable prognostic factors for survivals. In non-SCs, Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, high PD-L1 expression, and normal alkaline phosphatase (ALP) levels favored better progression-free survival (PFS), while EGFR mutants indicated poor PFS (P<0.05).ConclusionsAmong patients treated with 1st-line immunotherapy, a higher HbA1c level (≥6.5%) indicated dismal OS, while history of DM, baseline blood glucose levels, and glucose changes during the treatment process were not significantly associated with any of the outcomes.

Programmed Death Ligand 1 (PD-L1) as a Therapeutic Target in Gestational Trophoblastic Neoplasia (GTN) (098)

<b>Objectives:</b> Despite early efficacy signals for anti-PD-L1/PD-1 immunotherapy in chemotherapy-resistant GTN, response rates are variable. Lack of consistent evaluation and reporting of trophoblast PD-L1 expression and other candidate predictive biomarkers makes developing a precise strategy for PD-L1/PD-1 blockade in the treatment of GTN challenging. We characterize trophoblast PD-L1 expression using the clinically applicable PD-L1 IHC 22C3 assay, tumor-infiltrating immune cell (TIIC) density and clinical outcomes in one of the largest GTN cohorts to date. <b>Methods:</b> Cases of paraffin-embedded primary tumors in our GTN library were used for this investigation (<i>n</i>=60). Immunohistochemistry (IHC) staining for PD-L1, CD68 (macrophages), CD8, CD4, and CD56 (NK cells) was performed on fresh-cut 4-mm tissue sections. Tumor proportion scores (TPS) were independently assigned by two gynecologic pathologists. Digital image analysis using QuPath v0.2.3 to average TIIC density in 3 40x hotspots per case was performed. Complete clinical data was possible for 18 patients. Descriptive statistics, Wilcoxon rank-sum test, and simple linear regression were used. <b>Results:</b> PD-L1 expression and TIIC density were quantified for all 60 cases of choriocarcinoma (CC, <i>n</i>=32), placental site trophoblastic tumor (PSTT, <i>n</i>=9), and epithelioid trophoblastic tumor (ETT, <i>n</i>=19). CC and PSTT have higher trophoblast PD-L1 expression than ETT; the median TPS for CC and PSTT was 85% (range: 0-98%) and 90% (range: 0-90%), compared to 35% (range: 0-100%) for ETT (p=0.02). CD68 monocytes were more abundant in CC and PSTT than ETT. CD8 cytotoxic T (p<0.01) and CD4 regulatory T (p=0.04) cell densities were higher in ETT. CD56 expression was associated with PD-L1 expression (slope=0.36, p=0.03). The Table summarizes the clinically annotated subset of patients. Similar patterns of PD-L1 expression/ TPS and TIICs were observed for CC and ETT; complete data were available for only two PSTT cases. Of the 15 patients who did not see anti-PD-L1/PD-1 treatment, seven (47%) would have been eligible based on a TPS of >0 and might have been offered it as an alternative to multi-agent chemotherapy or fertility loss. Two (PSTT case 16 and ETT case 17) of the three patients who received salvage anti-PD-1 therapy had durable complete responses. The third case (ETT case 18) had a complete response but then progressed after two years. All three had above-median TPS scores for their histologic subtypes and had moderate to high levels of CD56 expression. The two patients without evidence of disease had above median levels of CD8 and CD68 for their subtype, while the patient who recurred had below-median levels of both immune markers. <b>Conclusions:</b> Contrary to the published literature, ubiquitously high trophoblastic PD-L1 expression was not observed using the clinically applicable PD-L1 IHC 22C3 assay. Rather, there is a wide range of PD-L1 expression, including some cases with a TPS score of 0%. We added three cases of non-CC treated with salvage anti-PD-L1/PD-1 therapy to the four reported to date. In these cases, tumor-infiltrating CD8, CD68, and CD56 cell density may influence anti-PD-1 efficacy. There may be an opportunity to spare GTN patients from toxicity and/or adverse outcomes by prescribing anti-PD-L1/PD-1 therapy earlier in their disease course.

Responses to the Tepotinib in Gastric Cancers with MET Amplification or MET Exon 14 Skipping Mutations and High Expression of Both PD-L1 and CD44.

Simple SummaryHigh MET copy-number variation (CNV) and high MET protein expression via MET exon 14 skipping mutation (METex14SM) are associated with tumorigenesis; however, METex14SM is rare in GC, so target therapy is rarely applicable. In this study, we analyzed GC panels using targeted next-generation sequencing in GC cell lines and found that tepotinib demonstrated therapeutic effects in MET-amplified GC and those with high expressions of PD-L1, CD44, and METex14SM. Our in vitro findings indicate that tepotinib prevents GC-associated MET amplification and MET mutation.Both MET exon 14 skipping mutation (METex14SM) and high copy-number variation (CNV) lead to enhanced carcinogenesis; additionally, programmed-death ligand 1 (PD-L1) is often upregulated in cancers. In this study, we characterized the expression of MET (including METex14SM), PD-L1, and CD44 in human gastric cancer (GC) cells as well as the differential susceptibility of these cells to tepotinib. Tepotinib treatments inhibited the growth of five GC cells in a dose-dependent manner with a concomitant induction of cell death. Tepotinib treatments also significantly reduced the expression of phospho-MET, total MET, c-Myc, VEGFR2, and Snail protein in SNU620, MKN45, and Hs746T cells. Notably, tepotinib significantly reduced the expression of CD44 and PD-L1 in METex14SM Hs746T cells. By contrast, tepotinib was only slightly active against SNU638 and KATO III cells. Migration was reduced to a greater extent in the tepotinib-treated group than in the control group. Tepotinib may have therapeutic effects on c-MET-amplified GC, a high expression of both PD-L1 and CD44, and METex14SM. Clinical studies are needed to confirm these therapeutic effects.

Impact of Programmed Death-ligand 1 Expression on Oncological Outcomes in Patients with Muscle-invasive Bladder Cancer Treated with Radiation-based Therapy

BackgroundNo biomarkers are recommended for patients undergoing radiation-based therapy (RT) for muscle-invasive bladder cancer (MIBC). ObjectiveWe aim to evaluate the predictive role of programmed death-ligand 1 (PD-L1) expression on the oncological outcomes of patients treated with RT for MIBC. Design, setting, and participantsA single-center retrospective analysis of tumor specimens collected through transurethral resection (TURBT) from 104 MIBC patients, implemented in a tissue microarray and stained with the SP263 PD-L1 clone (Ventana Medical Systems, Tucson, AZ, USA), was conducted. Two reviewers measured the PD-L1 H-score for tumor and immune cells. InterventionRT (maximal TURBT followed by radiation and concurrent chemotherapy when eligible). Outcome measurements and statistical analysisLogistic and Cox regression models were used to predict 3-mo complete response (CR) and overall survival (OS) after RT, respectively. Results and limitationsA total of 88 (85%) patients had cT2 disease and 39 (37.5%) had high immune cell PD-L1 expression. A CR was achieved in 68 (65%) patients. On the multivariable analysis (MVA), a higher clinical stage (p = 0.02) and a low immune cell PD-L1 H-score (p = 0.02) were associated with a decreased CR after RT. The median time to death was 43 mo (95% confidence interval 20–66). On Cox MVA, a high immune cell PD-L1 H-score (p = 0.0017) was associated with better OS, independently of performance status (p = 0.0005) or tumor stage (p = 0.0013). A high tumor cell PD-L1 H-score was not an independent predictor of CR or OS. Limitations of the study include the retrospective design. ConclusionsMIBC patients with high PD-L1 expression on immune cells appear to have better oncological outcomes following RT. Our results may aid in patient stratification for future clinical trial design. Patient summaryIn this report, we evaluated the role of programmed death-ligand 1 (PD-L1) expressed on tumor and immune cells in the tumor microenvironment for patients treated with a bladder-sparing regimen. We found that PD-L1 overexpression on immune cells is able to predict a better response to radiation-based therapy.

Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline.

To provide evidence-based recommendations updating the 2020 ASCO and Ontario Health (Cancer Care Ontario) guideline on systemic therapy for patients with stage IV non-small-cell lung cancer without driver alterations. ASCO updated recommendations on the basis of an ongoing systematic review of randomized clinical trials from 2018 to 2021. This guideline update reflects changes in evidence since the previous update. Five randomized clinical trials provide the evidence base. Outcomes of interest include efficacy and safety. In addition to 2020 options for patients with high programmed death ligand-1 (PD-L1) expression (tumor proportion score [TPS] ≥ 50%), nonsquamous cell carcinoma (non-SCC), and performance status (PS) 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression (TPS ≥ 50%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilumumab alone or nivolumab and ipilimumab plus chemotherapy. With negative (0%) and low positive PD-L1 expression (TPS 1%-49%), non-SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or nivolumab and ipilimumab plus chemotherapy. With high PD-L1 expression, SCC, and PS 0-1, clinicians may offer single-agent atezolizumab. With high PD-L1 expression, squamous cell carcinoma (SCC), and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With negative and low positive PD-L1 expression, SCC, and PS 0-1, clinicians may offer nivolumab and ipilimumab alone or in combination with two cycles of platinum-based chemotherapy. With non-SCC who received an immune checkpoint inhibitor and chemotherapy as first-line therapy, clinicians may offer second-line paclitaxel plus bevacizumab. With non-SCC, who received chemotherapy with or without bevacizumab and immune checkpoint inhibitor therapy, clinicians should offer the options of third-line single-agent pemetrexed, docetaxel, or paclitaxel plus bevacizumab.Additional information is available at www.asco.org/thoracic-cancer-guidelines.

PD-L1 regulates cell proliferation and apoptosis in acute myeloid leukemia by activating PI3K-AKT signaling pathway

As immune checkpoint inhibitors (ICIs) continue to advance, more evidence has emerged that anti-PD-1/PD-L1 immunotherapy is an effective treatment against cancers. Known as the programmed death ligand-1 (PD-L1), this co-inhibitory ligand contributes to T cell exhaustion by interacting with programmed death-1 (PD-1) receptor. However, cancer-intrinsic signaling pathways of the PD-L1 molecule are not well elucidated. Therefore, the present study aimed to evaluate the regulatory network of PD-L1 and lay the basis of successful use of anti-PD-L1 immunotherapy in acute myeloid leukemia (AML). Data for AML patients were extracted from TCGA and GTEx databases. The downstream signaling pathways of PD-L1 were identified via Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The key PD-L1 related genes were selected by weighted gene co-expression network analysis (WGCNA), MCC algorithm and Molecular Complex Detection (MCODE). The CCK-8 assay was used to assess cell proliferation. Flow cytometry was used to determine cell apoptosis and cell cycle. Western blotting was used to identify the expression of the PI3K-AKT signaling pathway. PD-L1 was shown to be elevated in AML patients when compared with the control group, and high PD-L1 expression was associated with poor overall survival rate. The ECM-receptor interaction, as well as the PI3K-AKT signaling pathway, were important PD-L1 downstream pathways. All three analyses found eight genes (ITGA2B, ITGB3, COL6A5, COL6A6, PF4, NMU, AGTR1, F2RL3) to be significantly associated with PD-L1. Knockdown of PD-L1 inhibited AML cell proliferation, induced cell apoptosis and G2/M cell cycle arrest. Importantly, PD-L1 knockdown reduced the expression of PI3K and p-AKT, but PD-L1 overexpression increased their expression. The current study elucidates the main regulatory network and downstream targets of PD-L1 in AML, assisting in the understanding of the underlying mechanism of anti-PD-1/PD-L1 immunotherapy and paving the way for clinical application of ICIs in AML.