Programmed Death-ligand 1 Expression Research Articles

PD-L1 and nectin-4 expression and genomic characterization of bladder cancer with divergent differentiation.

Bladder cancer with divergent differentiation (BCDD) comprises a heterogenous group of tumors with a poor prognosis, and differential expression of nectin-4 and programmed death ligand-1 (PD-L1) has been reported in BCDD. Importantly, nectin-4 expression in bladder cancer is associated with response to enfortumab vedotin, and PD-L1 expression is associated with responses to immune checkpoint inhibitors (ICIs). The authors conducted a retrospective review identifying 117 patients with advanced or metastatic BCDD who were treated at Winship Cancer Institute from 2011 to 2021. They performed immunohistochemistry staining for nectin-4 and PD-L1 expression by histologic subtype as well as genomic analysis of these patients, including RNA sequencing, whole-exome sequencing, and fusion detection analysis as well as a subgroup genomic analysis of patients with BCDD who received ICIs. The results indicated that nectin-4 expression was highest in the groups who had the squamous and plasmacytoid subtypes, whereas the group that had the sarcomatoid subtype (70.8%) had the highest proportion of PD-L1-positive patients. Genomic analysis yielded several key findings, including a 50% RB1 mutation rate in patients who had small cell BCDD, targetable PIK3CA mutations across multiple subtypes of BCDD, and significantly higher expression of TEC in responders to ICIs. In this study, the authors identified clinically relevant data on nectin-4 and PD-L1 expression in patients with rare bladder tumors. They also identified several novel findings in the genomic analysis that highlight the role of precision medicine in this population of patients. Larger, prospective studies are needed to validate these hypothesis-generating data.

Immunohistochemical factors of prognosis of immunotherapy for metastatic melanoma: А prospective and retrospective study

Introduction. Anti-PD-1 immunotherapy (IT) is becoming the standard treatment for patients with metastatic melanoma. However, immune checkpoint inhibitors are only effective in a fraction of patients, and studies examining biological markers and their correlation with clinical efficacy are insufficient to draw unambiguous conclusions. Aim. To improve the outcomes of the first-line therapy for disseminated melanoma based on identifying clinical and immunohistochemical predictors of IT efficacy. Materials and methods. Data from 130 patients who were treated with immune checkpoint inhibitors (nivolumab or prolgolimab) in the first-line therapy for disseminated melanoma between 2017 and 2024 were analyzed. Results. Improvement was observed in 24 patients (18.4%): complete response in 18 patients (13.8%), partial response in 6 (4.6%), and stabilization in 71 (54.6%) patients. Progression was reported in 31 (24%) patients. Death occurred in 4 (3%) cases during IT with prolgolimab due to disease progression. The two-year disease-free survival (DFS) during IT was 53% (95% confidence interval [CI] 42–67), p=0.63; the median 2-year overall survival was not reached. In the immunohistochemical study, 47 (63.5%) patients had a predominance of tumor infiltration with CD8 lymphocytes over CD4, regardless of the IT type: 2-year DFS 82% (95% CI 70–96) vs 13% (95% CI 2.7–64) in the absence of CD8 predominance over CD4, p=0.0001; the median DFS was not reached in patients with the predominance of CD8 lymphocytes tumor infiltration over CD4 compared to the other group – 7.6 months in the absence of this feature (95% CI 5.8–0), p=0.001. The peritumoral location of the immune lymphoid infiltrate was observed in all 74 (100%) patients, and the intratumoral location was less common (52 patients, 70%). In the presence of both periand intratumoral location of the immune infiltrate, the 2-year DFS was 83% (95% CI 70–98) compared to the group of patients in whom no intratumoral location was detected – 5.5% (95% CI 0.8–36), p0.0001. The expression of programmed cell death ligand 1 (PD-L1) level 10% was observed in 47 (63.5%) patients. With this level of PD-L1 expression, the one-year DFS was 91% (95% CI 83–100) compared to 29% (95% CI 15–57) with a lower level of PD-L1 expression, p0.0001; the median DFS is reached, and in the group 2, DFS was only 6.6 months. In the case of PD-L110%, the 2-year DFS was high at 78% (95% CI 63–100), p0.0001. Conclusion. Based on the study's results, it can be assumed that immunohistochemical characteristics such as a PD-L1 expression level 10%, the simultaneous presence of periand intratumoral lymphoid tumor infiltration, and the predominance of CD8 over CD4 can be considered predictors of IT efficacy with nivolumab and prolgolimab.

Targeting Nuclear Receptor Coactivator SRC-1 Prevents Colorectal Cancer Immune Escape by Reducing Transcription and Protein Stability of PD-L1.

Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8+ T cells. Genetic ablation of SRC-1 in mice also decreases PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, these findings highlight a crucial role of SRC-1 in regulating PD-L1 expression and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.

Optimizing immunofluorescence with high-dynamic-range imaging to enhance PD-L1 expression evaluation for 3D pathology assessment from NSCLC tumor tissue

Assessing programmed death ligand 1 (PD-L1) expression through immunohistochemistry (IHC) is the golden standard in predicting immunotherapy response of non-small cell lung cancer (NSCLC). However, observation of heterogeneous PD-L1 distribution in tumor space is a challenge using IHC only. Meanwhile, immunofluorescence (IF) could support both planar and three-dimensional (3D) histological analyses by combining tissue optical clearing with confocal microscopy. We optimized clinical tissue preparation for the IF assay focusing on staining, imaging, and post-processing to achieve quality identical to traditional IHC assay. To overcome limited dynamic range of the fluorescence microscope’s detection system, we incorporated a high dynamic range (HDR) algorithm to restore the post imaging IF expression pattern and further 3D IF images. Following HDR processing, a noticeable improvement in the accuracy of diagnosis (85.7%) was achieved using IF images by pathologists. Moreover, 3D IF images revealed a 25% change in tumor proportion score for PD-L1 expression at various depths within tumors. We have established an optimal and reproducible process for PD-L1 IF images in NSCLC, yielding high quality data comparable to traditional IHC assays. The ability to discern accurate spatial PD-L1 distribution through 3D pathology analysis could provide more precise evaluation and prediction for immunotherapy targeting advanced NSCLC.

Immune cells and checkpoints in pancreatic adenocarcinoma: Association with clinical and pathological characteristics.

Pancreatic adenocarcinoma is an extremely aggressive neoplasm, with many challenges to be overcome in order to achieve a truly effective treatment. It is characterized by a mostly immunosuppressed environment, with dysfunctional immune cells and active immunoinhibitory pathways that favor tumor evasion and progression. Thus, the study and understanding of the tumor microenvironment and the various cells subtypes and their functional capacities are essential to achieve more effective treatments, especially with the use of new immunotherapeutics. Seventy cases of pancreatic adenocarcinoma divided into two groups 43 with resectable disease and 27 with unresectable disease were analyzed using immunohistochemical methods regarding the expression of programmed cell death ligand 1 (PD-L1), programmed cell death ligand 2 (PD-L2), and human leukocyte antigen G (HLA-G) molecules as well as the populations of CD4+ and CD8+ T lymphocytes, regulatory T cells (Tregs), and M2 macrophages (MM2). Several statistical tests, including multivariate analyses, were performed to examine how those immune cells and immunoinhibitory molecules impact the evolution and prognosis of pancreatic adenocarcinoma. CD8+ T lymphocytes and M2 macrophages predominated in the group operated on, and PD-L2 expression predominated in the unresectable group. PD-L2 was associated with T stage, lymph node metastasis, and clinical staging, while in survival analysis, PD-L2 and HLA-G were associated with a shorter survival. In the inoperable cases, Tregs cells, MM2, PD-L1, PD-L2, and HLA-G were positively correlated. PD-L2 and HLA-G expression correlated with worse survival in the cases studied. Tumor microenvironment was characterized by a tolerant and immunosuppressed pattern, mainly in unresectable lesions, where a broad positive influence was observed between immunoinhibitory cells and immune checkpoint proteins expressed by tumor cells.

Patterns and prognostic values of programmed cell death-ligand 1 expression and CD8 + T-cell infiltration in small cell carcinoma of the esophagus: a retrospective analysis of 34 years of National Cancer Center data in China.

Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8 + T cell in SCCE for the first time. Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient's Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. No patients had PD-L1 expressed in their tumor cells. PD-L1 + expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68 + monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression ( Ptrend <0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.

Correlation of PD-L1 expression with CD8+ T cells and oxidative stress-related molecules NRF2 and NQO1 in esophageal squamous cell carcinoma.

Oxidative stress and the immune microenvironment both contribute to the pathogenesis of esophageal squamous cell carcinoma (ESCC). However, their interrelationships remain poorly understood. We aimed to examine the status of key molecules involved in oxidative stress and the immune microenvironment, as well as their relationships with each other and with clinicopathological features and prognosis in ESCC. The expression of programmed death-ligand 1 (PD-L1), CD8, nuclear factor erythroid-2 related factor-2 (NRF2), and NAD(P)H quinone oxidoreductase 1 (NQO1) was detected using immunohistochemistry in tissue samples from 176 patients with ESCC. We employed both combined positive score (CPS) and tumor proportion score (TPS) to evaluate PD-L1 expression and found a positive correlation between CPS and TPS. Notably, PD-L1 expression, as assessed by either CPS or TPS, was positively correlated with both NRF2 nuclear score and NQO1 score in stage II-IV ESCC. We also observed a positive correlation between the density of CD8+ T cells and PD-L1 expression. Furthermore, high levels of PD-L1 CPS, but not TPS, were associated with advanced TNM stage and lymph node metastases. Moreover, both PD-L1 CPS and the nuclear expression of NRF2 were found to be predictive of shorter overall survival in stage II-IV ESCC. By using the Mandard-tumor regression grading (TRG) system to evaluate the pathological response of tumors to neoadjuvant chemotherapy (NACT), we found that the TRG-5 group had higher NRF2 nuclear score, PD-L1 CPS, and TPS in pre-NACT biopsy samples compared with the TRG-3 + 4 group. The NQO1 scores of post-NACT surgical specimens were significantly higher in the TRG-5 group than in the TRG 3 + 4 group. In conclusion, the expression of PD-L1 is associated with aberrant NRF2 signaling pathway, advanced TNM stage, lymph node metastases, and unfavorable prognosis. The dysregulation of PD-L1 and aberrant activation of the NRF2 signaling pathway are implicated in resistance to NACT. Our findings shed light on the complex interrelationships between oxidative stress and the immune microenvironment in ESCC, which may have implications for personalized therapies and improved patient outcomes.

Radiomics Models Derived From Arterial-Phase-Enhanced CT Reliably Predict Both PD-L1 Expression and Immunotherapy Prognosis in Non-small Cell Lung Cancer: A Retrospective, Multicenter Cohort Study

Rationale and objectivesImmune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC) and programmed cell death-ligand 1 (PD-L1) is a companion biomarker. This study aims to use baseline arterial phase enhanced CT (APECT) to construct efficient radiomic models for predicting PD-L1 expression and immunotherapy prognosis in NSCLC. Materials and methodsWe extracted radiomics features from the baseline APECT images of 204 patients enrolled in a published multicenter clinical trial that commenced on August 23, 2018, and concluded on November 15, 2019 (ClinicalTrials.gov: NCT03607539). Of these patients, 146 patients from selected centers were assigned to the training cohort. The least absolute shrinkage and selection operator (LASSO) method was used to reduce dimensionality of radiomics features and calculate tumor scores. Models were created using naive bayes, decision trees, XGBoost, and random forest algorithms according to tumor scores. These models were then validated in an independent validation cohort comprising 58 patients from the remaining centers. ResultsThe random forest algorithm outperformed the other methods. In the three-classification scenario, the random forest model achieving the area under the curve (AUC) values of 0.98 and 0.94 in the training and validation cohorts, respectively. In the two-classification scenario, the random forest model achieved AUCs of 0.99 (95%CI: 0.97-1.0, P < 0.0001) and 0.93 (95%CI: 0.83-0.98, P < 0.0001) in the training and validation cohorts, respectively. Furthermore, patients classified as PD-L1 high-expression by this model can predict treatment response (AUC = 0.859, 95%CI: 0.7 – 0.96, P < 0.001) and improved survival (HR = 0.2, 95%CI: 0.08-0.53, P = 0.001) only in validation sintilimab arm. ConclusionRadiomics models based on APECT represent a potential noninvasive approach to robustly predict PD-L1 expression and ICI treatment outcomes in patients with NSCLC, which could significantly improve precision cancer immunotherapy.

Guanylate binding protein 5 is an immune-related biomarker of oral squamous cell carcinoma: A retrospective prognostic study with bioinformatic analysis.

Cancer utilizes immunosuppressive mechanisms to create a tumor microenvironment favorable for its progression. The purpose of this study is to histologically characterize the immunological properties of the tumor microenvironment of oral squamous cell carcinoma (OSCC) and identify key molecules involved in the immunological microenvironment and patient prognosis. First, overlapping differentially expressed genes (DEGs) were screened from OSCC transcriptome data in public databases. Correlation analysis of DEGs with known immune-related genes identified genes involved in the immune microenvironment of OSCC. Next, stromal patterns of tumor were classified and immunohistochemical staining was performed for immune cell markers (CD3, CD4, Foxp3, CD8, CD20, CD68, and CD163), programmed death-ligand 1 (PD-L1), and guanylate binding protein 5 (GBP5) in resected specimens obtained from 110 patients with OSCC who underwent resection. Correlations between each factor and their prognostic impact were analyzed. Among the novel OSCC-specific immune-related genes screened (including ADAMDEC1, CXCL9, CXCL13, DPT, GBP5, IDO1, and PLA2G7), GBP5 was selected as the target gene. Histopathologic analysis showed that multiple T-cell subsets and CD20-positive cells were less common in the advanced stages, whereas CD163-positive cells were more common in advanced stages. The immature type in the stromal pattern category was associated with less immune cell infiltration, lower expression of PD-L1 in immune cells, lower expression of GBP5 in the stroma, and shorter overall survival and recurrence-free survival. Expression of GBP5 in the tumor and stroma correlated with immune cell infiltration of tumors and PD-L1 expression in tumor and immune cells. Patients with low tumor GBP5 expression and high stromal expression had significantly longer overall survival and recurrence-free survival. The stromal pattern category may reflect both invasive and immunomodulatory potentials of cancer-associated fibroblasts in OSCC. GBP5 has been suggested as a potential biomarker to predict the prognosis and therapeutic efficacy of immune checkpoint inhibitors.

PD-L1 expression from surgically resected lung tumors predictive of early progression in patients previously treated with targeted therapy for initially unresectable non-small cell lung cancer.

Recent evidences showed that resection of lung tumor post-targeted therapy has shown progression-free survival (PFS) benefits in initially unresectable patients. The aim of this study is to evaluate pathologic findings of resected lung tumor samples in patients who have undergone prior epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) treatment, and also to assess the prognostic factors related to outcomes after resection. The deidentified data of non-small cell lung cancer (NSCLC) patients admitted to seven university hospitals affiliated with the Catholic University of Korea were obtained from the Clinical Data Warehouse (CDW) database. Among screened patients, 40 individuals who had previously undergone targeted therapies and later received surgical resection of a primary lung tumor were evaluated for the study. All 40 patients were diagnosed with adenocarcinoma. Of these, 36 with EGFR mutations received prior EGFR TKI treatment. Only one postoperative complication, atrial fibrillation, was observed. At the time of resection, 19 patients showed primary lung tumor size regressing or unchanged, while 21 patients showed primary lung tumor regrowth or new lesions being developed before the resection. The group with no programmed death-ligand 1 (PD-L1) expression from resected samples showed significantly better post-resection PFS when compared to the other group (P=0.01). In the Model II multivariate analysis for post-resection PFS, PD-L1 detection from the resected sample was significantly associated with PFS [P=0.03; hazard ratio (HR) =5.465; 95% confidence interval (CI): 1.200-24.885]. Furthermore, an increase in PD-L1 expression compared to the baseline value was associated with an increasing lung tumor burden at the time of resection (P=0.03). Resected specimen following targeted therapy can provide valuable clinical information that can be used to predict the prognosis of patients with initially unresectable NSCLC.

Comparing the Effectiveness of Afatinib and Osimertinib for Patients With PD-L1-positive EGFR-mutant Non-small Cell Carcinoma.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are effective for treating non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, higher tumor programmed death ligand-1 (PD-L1) expression is associated with a poor response to EGFR-TKIs, and information on the comparison between afatinib and osimertinib in PD-L1-positive EGFR-mutant NSCLC is scarce. We retrospectively analyzed data of patients with PD-L1-positive EGFR-mutant NSCLC to compare the effectiveness of afatinib and osimertinib. A total of 177 patients were included in the study. The Cox proportion hazard model was adjusted for age, sex, performance status, EGFR mutation status, PD-L1 expression level, and brain metastasis, revealing that there was no significant difference in risk for progression [hazard ratio (HR)=0.99, 95% confidence interval (CI)=0.64-1.53] or death (HR=0.96, 95% CI=0.54-1.73) between afatinib and osimertinib. In conclusion, the EGFR-TKI treatment duration and overall survival after the treatment with afatinib or osimertinib were similar in patients with PD-L1-positive EGFR-mutant NSCLC in the present study.

Real-world first-line treatment with pembrolizumab for non-small cell lung carcinoma with high PD-L1 expression: Updated analysis.

Selecting pembrolizumab monotherapy (MONO) or pembrolizumab plus platinum-based chemotherapy (COMB) for patients with nonsmall cell lung cancer (NSCLC) and high programmed death-ligand 1 (PD-L1) expression is an important issue in clinical practice. We previously conducted a retrospective multicenter observational study of patients with NSCLC and high PD-L1 expression who received MONO or COMB as a first-line treatment. Here, we report updated data and evaluate the long-term outcomes. We performed a retrospective multicenter study of 298 patients with NSCLC and high PD-L1 expression who received MONO or COMB as first-line treatment between December 2018 and January 2020. We reviewed the medical records and assessed the clinical efficacy and toxicity using a prolonged data cutoff. In total, 164 (median age: 74 years) and 134 (median age: 68 years) patients received MONO and COMB, respectively; patients who received COMB were younger and had better performance statuses (0-1). At the prolonged data cutoff, the median follow-up was 20.2 (range: 0.1-41.4) months. The median progression-free survivals were 7.5 and 13.1 months, and overall survivals (OSs) were 17.2 and 33.7 months for MONO and COMB, respectively. Treatment discontinuation rates were 21.9% and 20.1% for the MONO and COMB, respectively. With prolonged follow-up, although COMB demonstrated an OS benefit and higher objective response rate than MONO, in the propensity score matching analysis COMB didn't demonstrate a significant benefit compared to the MONO. COMB may be effective as a first-line treatment for NSCLC with high PD-L1 expression in a selected subset of patients.

Failure of the PD-1 Blocking Agent Pembrolizumab to Benefit a Patient with Renal Squamous Cell Cancer.

Renal squamous cell carcinoma (SCC) is a neoplasm with an extremely rare occurrence compared to other renal malignancies. The classic presentation includes a palpable mass and flank pain; however, the presentation is seldom non-specific. Our study describes the significance of programmed death ligand-1 (PD-L1) expression in renal cancer and its association with clinical outcomes, alongside available treatment options. An 80-year-old female with a history of hypertension and cerebral aneurysm presented with right flank pain and blood in urine and was diagnosed with pyelonephritis and left renal mass/phlegmon. A biopsy revealed SCC of the kidney with metastasis to the lung and aortocaval lymph node. Positron emission tomography (PET) scan confirmed malignancy in the kidney and lung. Treatment with pemrolizumab and carboplatin plus paclitaxel was initiated but poorly tolerated as the haemoglobin dropped rapidly. SCC poses a diagnostic challenge due to its rarity and non-specific symptoms, often leading to advanced stage diagnosis. PD-L1 expression is pivotal in assessing tumour aggressiveness and prognosis. PD-L1 inhibitors offer promise, but their efficacy in renal SCC warrants further investigation. Radical nephrectomy and systemic chemotherapy show potential in advanced cases, necessitating vigilant management of treatment-related side effects. This case emphasises the need for ongoing research to refine therapeutic approaches and enhance outcomes in renal SCC patients. PD-L1 expression is pivotal in assessing tumour aggressiveness and prognosis of renal cell carcinoma.PD-L1 inhibitors hold promise as a therapeutic intervention in renal squamous cancer.Radical nephrectomy and systemic chemotherapy show potential in managing advanced renal cancer.

Analysis of Treatment Response With Proteins Related to Tumor Immunity in Postoperative Irradiated Cervical Cancer Patients.

This study evaluated the association between programmed cell death-ligand 1 (PD-L1) and prognosis in patients with cervical cancer treated with postoperative radiation and the impact of neoadjuvant chemotherapy (NAC) on this association. Immunohistochemical analysis was performed on biopsy specimens from 42 patients who did not receive NAC and from paired samples before (biopsies) and after (resected tissues) chemotherapy from 46 patients who received NAC to determine the association of PD-L1 with radiotherapy outcomes. In the non-NAC group, patients with ≥10% PD-L1-expressing tumor cells prior to treatment had better recurrence-free survival (RFS) than those with <10% PD-L1-expressing tumor cells (p=0.001). In the NAC group, RFS was significantly lower (p=0.005) in the group with a ≥5% reduction of PD-L1 expression in tumor cells after chemotherapy than in those with <5% reduction. In multivariate analysis, only PD-L1 expression (non-NAC group) and the change in PD-L1 expression (NAC group) were associated with RFS. Low PD-L1 expression in a cervical tumor prior to treatment was identified as a risk factor for a poor outcome after postoperative radiotherapy. Furthermore, NAC induces an immunological shift that reduces PD-L1 levels in tumor cells, thereby negatively impacting treatment outcomes.

Targeted protein degradation combined with PET imaging reveals the role of host PD-L1 in determining anti-PD-1 therapy efficacy.

Immunohistochemical staining of programmed death-ligand 1 (PD-L1) in tumor biopsies acquired through invasive procedures is routinely employed in clinical practice to identify patients who are most likely to benefit from anti-programmed cell death protein 1 (PD-1) therapy. Nevertheless, PD-L1 expression is observed in various cellular subsets within tumors and their microenvironments, including tumor cells, dendritic cells, and macrophages. The impact of PD-L1 expression across these different cell types on the responsiveness to anti-PD-1 treatment is yet to be fully understood. We synthesized polymer-based lysosome-targeting chimeras (LYTACs) that incorporate both PD-L1-targeting motifs and liver cell-specific asialoglycoprotein receptor (ASGPR) recognition elements. Small-animal positron emission tomography (PET) imaging of PD-L1 expression was also conducted using a PD-L1-specific radiotracer 89Zr-αPD-L1/Fab. The PD-L1 LYTAC platform was capable of specifically degrading PD-L1 expressed on liver cancer cells through the lysosomal degradation pathway via ASGPR without impacting the PD-L1 expression on host cells. When coupled with whole-body PD-L1 PET imaging, our studies revealed that host cell PD-L1, rather than tumor cell PD-L1, is pivotal in the antitumor response to anti-PD-1 therapy in a mouse model of liver cancer. The LYTAC strategy, enhanced by PET imaging, has the potential to surmount the limitations of knockout mouse models and to provide a versatile approach for the selective degradation of target proteins in vivo. This could significantly aid in the investigation of the roles and mechanisms of protein functions associated with specific cell subsets in living subjects.

PLA2G2D promotes immune escape in non-small cell lung cancer by regulating T cell immune function through PD-L1-expressing extracellular vesicles.

It is urgent to explore factors affecting immunotherapy efficacy to benefit non-small cell lung cancer (NSCLC) patient survival. Bioinformatics predicted genes associated with programmed cell death ligand 1 (PD-L1) expression and analysed phospholipase A2 group IID (PLA2G2D) expression in NSCLC. BODIPY 493/503 dye staining and kits detected lipids, triglycerides, and phospholipids in H1299 cells, respectively. Extracellular vesicles (EVs) were extracted for morphology and size assessment using electron microscopy. Western blot assayed CD9, CD63, HSP90, EVs-PD-L1, PD-L1, and PLA2G2D expression. CCK-8, LDH, and ELISA tested proliferation and toxicity of CD8+ T cells, interleukin-2, and interferon-gamma secretion, respectively. PLA2G2D, PD-L1, and Ki67 expression was detected by immunohistochemistry. Immunofluorescence assayed PLA2G2D localisation and CD8+ T cell content. Flow cytometry assessed PD-L1 and CD8 expression. In NSCLC, upregulated EVs-PD-L1 and clinical characteristics showed a strong correlation. H1299 cells with overexpression PD-L1 significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin-2 and interferon-gamma levels. Bioinformatics revealed positive correlations between PLA2G2D and overexpressed PD-L1. PLA2G2D was expressed in macrophages and dendritic cells in NSCLC tissue. Overexpression PLA2G2D (oe-PLA2G2D) increased lipids, triglycerides, and phospholipids contents in H1299 cells. oe-PLA2G2D significantly reduced proliferation, toxicity of CD8+ T cells, and interleukin-2 and interferon-gamma levels. si-PD-L1 restored inhibition of oe-PLA2G2D on CD8+ T cells. oe-PLA2G2D significantly increased mice tumour volume and weight, upregulated expression of blood EVs-PD-L1 and tissue PD-L1, PLA2G2D, Ki67, and decreased CD8+ T cell content. PLA2G2D facilitated immune escape in NSCLC by regulating CD8+ T cell immune function by upregulating EVs-PD-L1.

Staphyloccocus aureus biofilm, in absence of planktonic bacteria, produces factors that activate counterbalancing inflammatory and immune-suppressive genes in human monocytes.

Staphyloccocus aureus (S. aureus) is a major bacterial pathogen in orthopedic periprosthetic joint infection (PJI). S. aureus forms biofilms that promote persistent infection by shielding bacteria from immune cells and inducing an antibiotic-tolerant metabolic state. We developed an in vitro system to study S. aureus biofilm interactions with primary human monocytes in the absence of planktonic bacteria. In line with previous in vivo data, S. aureus biofilm induced expression of inflammatory genes such as TNF and IL1B, and their anti-inflammatory counter-regulator IL10. S. aureus biofilm also activated expression of PD-1 ligands, and IL-1RA, molecules that have the potential to suppress T cell function or differentiation of protective Th17 cells. Gene induction did not require monocyte:biofilm contact and was mediated by a soluble factor(s) produced by biofilm-encased bacteria that was heat resistant and >3 kD in size. Activation of suppressive genes by biofilm was sensitive to suppression by Jak kinase inhibition. These results support an evolving paradigm that biofilm plays an active role in modulating immune responses, and suggest this occurs via production of a soluble vita-pathogen-associated molecular pattern, a molecule that signals microbial viability. Induction of T cell suppressive genes by S. aureus biofilm provides insights into mechanisms that can suppress T cell immunity in PJI.

Consistent efficacy of hepatic artery infusion chemotherapy irrespective of PD‑L1 positivity in unresectable hepatocellular carcinoma.

Atezolizumab/bevacizumab is the first line of treatment for unresectable hepatocellular carcinoma (HCC), combining immune checkpoint inhibitor and anti-VEGF monoclonal antibodies. Hepatic arterial infusion chemotherapy (HAIC) is administered when the above-described combination fails to confer sufficient clinical benefit. The present study aimed to explore the association between tumor programmed cell death-ligand 1 (PD-L1) positivity and HAIC response. A total of 40 patients with HCC who had undergone HAIC with available biopsy samples obtained between January 2020 and May 2023 were retrospectively enrolled. Tumor response, progression-free survival (PFS), disease control rate (DCR) and overall survival (OS) were evaluated. PD-L1 expression in tumor samples was assessed using a combined positivity score. The response rates of HAIC-treated patients with advanced HCC after failure of atezolizumab/bevacizumab combination therapy were recorded. OS (P=0.9717) and PFS (P=0.4194) did not differ between patients with and without PD-L1 positivity. The objective response rate (P=0.7830) and DCR (P=0.7020) also did not differ based on PD-L1 status. In conclusion, the current findings highlight the consistent efficacy of HAIC, regardless of PD-L1 positivity.

Circulating receptor activator of nuclear factor kappa-B ligand (RANKL) levels predict response to immune checkpoint inhibitors in advanced non-small cell lung cancer (NSCLC)

BackgroundReceptor activator of nuclear factor kappa-B ligand (RANKL) can directly promote tumor growth and indirectly support tumor immune evasion by altering the tumor microenvironment and immune cell responses. This study...

Programmed Cell Death Ligand 1 (PD-L1) Immunohistochemical Expression in Advanced Urothelial Bladder Carcinoma: An Updated Review with Clinical and Pathological Implications.

The management of advanced bladder carcinoma involves a multidisciplinary approach, but the prognosis remains poor for many patients. The immune system plays a crucial role in this disease, influencing both tumor development and response to treatment, and exploiting the immune system against the tumor can be a valuable strategy to destroy neoplastic cells. This is the biological principle underlying Bacillus Calmette-Guérin (BCG) use and, more recently, immune checkpoint inhibitors (ICIs), like PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) inhibitors. In fact, one of the best studied immune checkpoints is represented by the PD-1/PD-L1 axis, which is a well-known immune escape system adopted by neoplastic bladder cells. PD-L1 expression has been associated with a higher pathologic stage and has shown prognostic value in bladder carcinoma. Interestingly, high-grade bladder cancers tend to express higher levels of PD-1 and PD-L1, suggesting a potential role of such an axis in mediating disease progression. Immunotherapy with PD-1 and PD-L1 inhibitors has therefore emerged as a valuable treatment option and has shown efficacy in advanced bladder cancer patients, with high PD-L1 expression levels associated with better treatment responses. Our review aims to provide a comprehensive overview of the role of PD-L1 in advanced bladder cancer, focusing on its implications for treatment decisions and the prediction of treatment response. Overall, our work aims to contribute to the understanding of PD-L1 as a predictive biomarker and highlight its role in shaping therapeutic approaches for advanced bladder cancer.