Programmed Death-ligand 1 Expression Research Articles

PD-L1 Expression Varies in Thyroid Cancer Types and Is Associated with Decreased Progression Free Survival (PFS) in Patients with Anaplastic Thyroid Cancer.

Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan-Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV). BRAF mutation was present in 41%, TERT in 30%, RAS in 19%, TP53 in 10%, and RET in 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p < 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity. TP53 mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%, p = 0.03), and RAS mutation was negatively associated with PD-L1 expression (8.1% vs. 24.2% p = 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p = 0.002). PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC.

Imaging PD-L1 in the brain-Journey from the lab to the clinic.

Immune checkpoint inhibitors (ICPIs) have proven to restore adaptive anti-tumor immunity in many cancers; however, no noteworthy therapeutic schedule has been established for patients with glioblastoma (GBM). High programmed death-ligand 1 (PD-L1) expression is associated with immunosuppressive and aggressive phenotypes in GBM. Presently, there is no standardized protocol for assessing PD-L1 expression levels to select patients and monitor their response to ICPI therapy. The aim of this study was to investigate the use of 89Zr-DFO-Atezolizumab to image the spatio-temporal distribution of PD-L1 in preclinical mouse models and in patients with newly diagnosed GBM treated with/without neoadjuvant Pembrolizumab. The immunoreactivity, binding affinity, and specificity of 89Zr-DFO-Atezolizumab were confirmed in vitro. Mice-bearing orthotopic GBM tumors or patients with newly diagnosed GBM treated with/without Pembrolizumab were intravenously injected with 89Zr-DFO-Atezolizumab, and PET/CT images were acquired 24, 48, and 72 hours in mice and at 48 and 72 post-injection in patients. Radioconjugate uptake was quantified in the tumor and healthy tissues. Ex vivo immunohistochemistry (IHC) and immunophenotyping were performed on mouse tumor samples or resected human tumors. 89Zr-DFO-Atezolizumab was prepared with high radiochemical purity (RCP > 99%). In vitro cell-associated radioactivity of 89Zr-DFO-Atezolizumab corroborated cell line PD-L1 expression. PD-L1 in mouse GBM tumors was detected with high specificity using 89Zr-DFO-Atezolizumab and radioconjugate uptake correlated with IHC. Patients experienced no 89Zr-DFO-Atezolizumab-related side effects. High 89Zr-DFO-Atezolizumab uptake was observed in patient tumors at 48 hours post-injection, however, the uptake varied between patients treated with/without Pembrolizumab. 89Zr-DFO-Atezolizumab can visualize distinct PD-L1 expression levels with high specificity in preclinical mouse models and in patients with GBM, whilst complementing ex vivo analysis.

Impact of TTF-1 Expression on the Prognostic Prediction of Patients with NSCLC with PD-L1 Expression Levels of 1% to 49%, Treated with Chemotherapy vs Chemoimmunotherapy: A Multicenter, Retrospective Study.

Thyroid transcription factor 1 (TTF-1) expression is a useful predictor of treatment efficacy in advanced non-squamous non-small-cell lung cancer (NSCLC). This study aimed to evaluate whether TTF-1 could predict the effectiveness of chemotherapy versus chemoimmunotherapy in patients with non-squamous NSCLC with programmed death ligand-1 (PD-L1) expression between 1% and 49%. We conducted a retrospective study of patients with NSCLC who were treated with chemotherapy or chemoimmunotherapy between March 2016 and May 2023. The patients had histologically confirmed NSCLC, stage III-IV or postoperative recurrence, TTF-1 measurements, and PD-L1 expression levels between 1% and 49%. Clinical data were analyzed to evaluate the effect of TTF-1 expression on treatment efficacy. This study included 283 of 624 patients. TTF-1-positive patients showed longer progression-free survival (PFS) and overall survival (OS) (PFS: 6.4 months [95% confidence interval (CI): 5.0-9.4] vs 4.1 months [95% CI: 2.7-6.1], p=0.03, OS: 17.9 months [95% CI: 15.2-28.1] vs 9.4 months [95% CI: 6.3-17.0], p<0.01) in the chemotherapy cohorts (n=93). In the chemoimmunotherapy cohort (n=190), there was no significant difference in PFS and OS between TTF-1-positive and negative groups (PFS: 7.6 months [95% CI: 6.4-11.0] vs 6.0 months [95% CI: 3.6-12.6], p=0.59, OS: 25.0 months [95% CI: 18.0-49.2] vs 21.3 months [95% CI: 9.8-28.8], p=0.09). In patients with NSCLC with PD-L1 expression between 1% and 49%, TTF-1 expression was a predictor of chemotherapeutic, but not chemoimmunotherapeutic, efficacy.

Identification of lncRNA dual targeting PD-L1 and PD-L2 as a novel prognostic predictor for gastric cancer.

Although breakthroughs have been achieved in gastric cancer (GC) therapy with immune checkpoint inhibitors (ICIs) targeting programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1), the acquisition of high response rate remains a huge challenge for clinicians. It is imperative to identify novel biomarkers for predicting response to immunotherapy and explore alternative therapeutic strategy for GC. The transcriptomic profiles and clinical information of GC patients from The Cancer Genome Atlas (TCGA)-stomach adenocarcinoma (STAD) database was used to screen differentially expressed lncRNAs between the tumor specimens and the paracancerous tissues. The TargetScan, miRDB and miRcode database were then utilized to construct competing endogenous RNA (ceRNA) networks and identify pivotal lncRNAs. An independent dataset from GEO (GSE70880) and 23 pairs of GC specimens of our cohort were subsequently performed for external validity. The relationship between clinical variables and gene expression were evaluated by Kruskal-wallis test and Wilcoxon signed-rank. The prognostic value of the candidate genes was assessed using Kaplan-Meier analysis and Cox regression models. CIBERSORT and Gene set enrichment analysis (GSEA) were used to determine immune cell infiltration. Gastric adenocarcinoma AGS cells and human embryonic kidney 293T (HEK293T) cells with knockdown of LINC01094 were generated by siRNA transfection, followed by detecting the alteration of the target miRNA and PD-L1/PD-L2 by RT-qPCR. Besides, the interaction between lncRNA and the miRNA-PD-L1/PD-L2 axis were verified by dual luciferase reporter assay. Twenty-two intersecting lncRNAs were identified to be PD-L1/PD-L2-related lncRNAs and LINC01094-miR-17-5p-PD-L1/PD-L2 was constructed as a potential ceRNA network. LINC01094 was increased in tumor specimens than adjacent normal samples and was positively associated with advanced tumor stages and EBV and MSI status. Furthermore, LINC01094 expression was an independent risk factor for poor overall survival (OS) in GC patients. CD8+ T cell exhaustion-related genes were enriched in high-LINC01094 tissues and high-PD-L2 group. A strong positive association of LINC01094 expression was established with M2 macrophages, IL-10+ TAM, as well as PD-L1 and PD-L2 levels, therefore a LINC01094-miR-17-5p-IL-10 network was proposed in macrophages. Using the exoRBase database, LINC01094 was assumed in blood exosomes of GC patients The results of knockdown experiments and luciferase reporter assays revealed that LINC01094 interacted with miR-17-5p and served as a miRNA sponge to regulate the expression of PD-L1 and PD-L2. LINC01094 dually regulates the expression of PD-L1 and PD-L2 and shapes the immunosuppressive tumor microenvironment via sponging miR-17-5p. LINC01094 may serve as a potential prognostic predictor and therapeutic target in GC.

The Prevalence of Programmed Death Ligand-1 (PD-L1) Expression in Non-Small Cell Lung Cancer: An Experience From Tertiary Care Hospital.

The prevalence of programmed cell death ligand-1(PD-L1) expression in non-small cell lung cancer (NSCLC) within unselected populations remains a research topic, though PD-L1 expression is important in guiding treatment decisions. The study objective was to ascertain the prevalence ofPD-L1 expression in patients of NSCLC and its association with clinicopathological characteristics and other gene mutations. Samples from patients with NSCLCs were analyzed in the study to determine the expression of PD-L1 through immunohistochemistry (IHC) using rabbit anti-human PDL-1/CD274 monoclonal antibody. Correlation analysis was done using Pearson's correlation coefficient (r). The study analyzed the association between PD-L1 expression and clinicopathological features. A total of 245 consecutive patients (154 men with 62.9%) with NSCLCs were subjected to PD-L1 testing, and 30.6% (n=75) were identified to be positive. It was twice as prevalent in men than women, with 154 men and 91 females, respectively. The PD-L1 expression failed to demonstrate any statistical significance with age, gender, smoking status, type of materials, location of biopsy, Eastern Cooperative Oncology Group Performance Status, and Epidermal Growth Factor Receptor mutation. High PD-L1 expression with tumor proportion score (TPS ≥ 50) was observed in 38.8% of patients, and it was more prevalent in female patients 29 (38.7%), smokers 59 (78.7%), stage IV tumors 44 (58.7%), and stage III tumors 28 (37.3%). Our study in Kerala showed PD-L1 expression in NSCLC patients, correlated with clinicopathologic factors. Males, COPD, ALK+, and advanced-stage tumors had higher expression. Females, smokers, poorly differentiated tumors, and stage IV tumors had high PD-L1.

Programmed Death-Ligand 1 (PD-L1) and Ki-67 Labeling Index: Correlation with Tumor Grade and Recurrence

Background: Meningiomas are common primary brain tumors with variable clinical behavior. While most are benign, a subset exhibits aggressive characteristics and a high recurrence rate. This study aimed to investigate the association of Programmed Death-Ligand 1 (PD-L1) and Ki-67 labeling index with histopathological grade and recurrence in meningioma. Methods: A retrospective study was conducted on 139 cases of meningioma diagnosed between January 2020 and December 2023. PD-L1 expression was evaluated using immunohistochemistry (IHC) and scored using the combined positive score (CPS). Ki-67 labeling index was determined as the percentage of tumor cells with positive nuclear staining. The association of PD-L1 and Ki-67 with histopathological grade and recurrence was analyzed. Results: PD-L1 expression was positive in 66.7% of cases and was significantly associated with recurrence (p = 0.006). A higher Ki-67 labeling index (&gt;4%) was observed in 68.9% of cases and was also significantly associated with recurrence (p = 0.013). No significant association was found between PD-L1 expression or Ki-67 labeling index and histopathological grade. Conclusion: PD-L1 expression and Ki-67 labeling index may serve as potential prognostic markers for predicting recurrence in meningioma. Further studies are needed to validate these findings and explore their potential therapeutic implications.

A case of successful conversion surgery for unresectable gallbladder cancer treated with durvalumab in combination with gemcitabine plus cisplatin.

We report a rare case of a patient with initially unresectable gallbladder cancer who underwent conversion surgery with durvalumab in combination with gemcitabine plus cisplatin and achieved an R0 resection. A 68year-old woman was found to have gallbladder cancer and multiple enlarged lymph nodes around the suprapancreatic rim and hepatic hilum invading the proper hepatic artery on computed tomography. The diagnosis was cT3cN2cM0, cStage IVB. After eight cycles of durvalumab in combination with gemcitabine plus cisplatin, all tumor markers became negative, and lymph node invasion of the hepatic artery disappeared. The patient underwent conversion surgery with gallbladder bed resection and regional lymph node dissection. There was no need for hepatic artery reconstruction. Pathology revealed ypT2aypN0ycM0, ypStage IIA, and radical resection was considered. Immunostaining of tissue collected at the time of endoscopic ultrasound-guided tissue acquisition revealed less than 1% programmed death ligand-1 expression. The patient continued adjuvant chemotherapy with single-agent durvalumab every 4weeks and maintained a relapse-free survival of 8months postoperatively. The utility of durvalumab in combination with gemcitabine plus cisplatin in unresectable gallbladder cancer independent of programmed death ligand-1 expression has been confirmed and may be an important option in future multimodal treatment, including conversion surgery.

PD-L1 protein expression in breast cancer

AimsThe immune checkpoint marker, Programmed cell death-ligand 1 (PD-L1), is expressed by both cancer epithelial cells and tumour-infiltrating immune cells (TICs) thus constituting a potential target for immunotherapy. This is...

Association between tumour-infiltrating lymphocyte-T CD8+ and programmed death-ligand 1 protein with the occurrence of metastasis in colorectal cancer patients: An observational study

Background: Tumour-infiltrating lymphocytes CD8+ (TILs CD8+) as an anticancer immune response and Programmed Death-Ligand 1 (PD-L1) as an immune checkpoint molecule expression are important in colorectal cancer (CRC) as their expression correlates with the immune status and the progression of cancer. The primary objective of this study is to examine the relationship between TILs CD8+ and PD-L1 expression levels and CRC metastasis to provide insights into the immune microenvironment’s role in CRC progression and metastasis, potentially improving patient outcomes and treatment response. Methods: This study was an observational study involving colorectal cancer patients who were treated at a tertiary hospital in Bandung, West Java, Indonesia. There were 40 patients included in the study. Tumour tissue samples were collected from patients, and immunohistochemical staining was performed to evaluate TILs CD8+ infiltration and PD-L1 expression levels. Clinical data, including metastasis occurrences, were collected from the cancer registry. Results: Analysis of TILs CD8+ and PD-L1 expression levels in CRC patients revealed significant findings regarding metastasis occurrence and cancer staging. There was a notable positive correlation between PD-L1 expression and TILs-CD8+ infiltration in the presence of distant metastasis and advanced cancer stage (p &lt; 0.05). However, no significant association was observed between TILs CD8 and PD-L1 expression levels and lymphatic metastasis. Conclusion: This study highlights the potential prognostic value of TILs CD8+ and PD-L1 expression levels in predicting CRC progression and metastasis. However, the lack of a significant correlation with lymphatic metastasis suggests the need for further investigation into the underlying mechanisms. Understanding the roles of PD-L1 and TILs-CD8+ expression in CRC metastasis may facilitate the development of targeted therapeutic strategies to improve patient outcomes.

PD-L1 expression in testicular germ cell tumors undergoing spontaneous regression.

Spontaneous regression of testicular germ cell tumors is a well-known phenomenon; however, the precise mechanisms of spontaneous regression are still unknown. Our study aimed to investigate programmed death-ligand 1 (PD-L1) expression in spontaneously regressed testicular germ cell tumors, exploring the link between the immune response and spontaneous regression. From a sample of 356 testicular germ cell tumors, we singled out 5 completely regressed and 6 partially regressed tumors. In four out of six cases with partial regression, a residual seminoma component was found, while in the remaining two cases, an embryonal carcinoma component was found. Comparisons were made with 20 pure seminomas and 20 mixed germ cell tumors (MGCTs). A semiquantitative immunohistochemical analysis of PD-L1 expression in tumor cells and intra/peritumoral lymphocytes was performed. There was no PD-L1 expression in tumors with complete regression. All partially regressed tumors showed expression in intra/peritumoral lymphocytes within the tumor remnants. Expression was significantly more frequent in pure seminomas compared to MGCTs (P = 0.004). A positive correlation was demonstrated between the seminoma component and the proportion of PD-L1 positive lymphocytes, with a Kendall's Tau-b coefficient of 0.626 (P < 0.001). Tumor cells showed PD-L1 expression in three MGCTs within the embryonal carcinoma component. Our results support an immunological mechanism of spontaneous tumor regression, with the strongest potential in testicular tumors containing seminoma components. However, further research is necessary to determine the role of PD-L1 ligand more precisely in the microenvironment of spontaneously regressed tumors.

Assessment of PD-L1 expression and tumour infiltrating lymphocytes in early-stage non-small cell lung carcinoma with artificial intelligence algorithms

AimsTo study programmed death ligand 1 (PD-L1) expression and tumour infiltrating lymphocytes (TILs) in patients with early-stage non-small cell lung carcinoma (NSCLC) with artificial intelligence (AI) algorithms.MethodsThe study included samples...

Efficacy of immune checkpoint inhibitors according to programmed cell death-ligand 1 expression in patients with non-small cell lung cancer and brain metastasis: A real-world prospective observational study.

Studies have shown the antitumor efficacy of immune checkpoint inhibitors (ICI) in patients with non-small cell lung cancer (NSCLC) and brain metastases (BM). However, it is unclear whether the efficacy of ICI is similar between patients with and without BM. It is yet unclear whether the efficacy of ICI in patients with BM increases with higher levels of programmed cell death-ligand 1 (PD-L1) expression, as observed in patients without BM. We compared the outcomes of ICI treatment between patients with and without BM using a cohort containing 1741 prospectively enrolled patients with lung cancer. We investigated whether there were differences in the outcomes of ICI based on PD-L1 expression levels between these patients. We enrolled 240 patients with NSCLC with or without BM who were treated with ICI or both chemotherapy and ICI. There were no significant differences in overall survival (OS) between all patients with or without BM (p = 0.489). However, OS was significantly shorter in patients with BM than in those without in the PD-L1 ≥ 50% group (16.5 M vs. 30.6 M, p = 0.003) but not in the PD-L1 ≥ 1% or negative group. BM was an independent poor prognostic factor for OS (hazard ratio: [95% confidence interval], 2.045; [1.058-3.953], p = 0.033) in the PD-L1 ≥ 50% group. Our study indicated that the outcomes of patients with or without BM treated with ICI were not significantly different. The efficacy of ICI in patients with PD-L1 expression ≥50% would be lower in patients with BM than in those without.

Clinical Outcomes of Maintenance Durvalumab After Definitive Concurrent Chemoradiotherapy in Unresectable Locally Advanced Stage III NSCLC According to EGFR and ALK Status: Korean Cancer Study Group LU-22-18

IntroductionThe role of maintenance durvalumab after definitive concurrent chemoradiotherapy (CCRT) in unresectable locally advanced NSCLC with EGFR mutation or ALK translocation remains unclear. We compared the effectiveness of durvalumab maintenance therapy in groups with EGFR/ALK wild-type versus those with EGFR or ALK mutations. MethodsIn this retrospective multicenter observational study, patients with locally advanced NSCLC without progression after CCRT followed by maintenance durvalumab and available molecular test results (EGFR and ALK) were eligible. The primary objective was to compare progression-free survival (PFS) between EGFR/ALK wild-type and EGFR or ALK mutant NSCLC. Secondary objectives include overall survival according to EGFR or ALK mutation and programmed death-ligand 1 (PD-L1) expression. ResultsAmong 339 patients, 279 had wild-type EGFR/ALK, 41 had EGFR mutations and 19 had ALK translocations. The median age was 68 years with 276 male individuals (81.4%) and 63 female individuals (18.6%), 165 (49.3%) had adenocarcinoma, 149 (44.5%) had squamous cell carcinoma, and 21 (6.3%) had other histologic types, 120 (35.4%) had stage IIIA, 168 (49.6%) stage IIIB, and 51 (15.0%) had stage IIIC. Most of the patients (n = 288, 85%) achieved partial response to CCRT, two (0.6%) had a complete response, and 49 patients (14.4%) had stable disease. Excluding four patients with unknown PD-L1 tumor proportion score (TPS), 16 (4.8%) had a PD-L1 TPS of 0, 168 (50.1%) had 1 to 49, and 151 (45.1%) had 50 or higher. The median PFS was 21.4 months (95% confidence interval [CI]: 17.3–25.3) for the EGFR/ALK wild-type group and 21.0 months (95% CI: 15.7–not available [NA]) for the EGFR or ALK mutant group with no significant difference (p = 0.74). Significant differences occurred in PFS on the basis of PD-L1 expression with values of 13.6 (95% CI: 10.5–NA), 18.7 (95% CI: 15.1–26.9), and 24.7 (95% CI: 20.7–NA) months for TPS of 0, 1–49, and 50 or higher, respectively (p = 0.02). ConclusionsDurvalumab maintenance therapy after definitive CCRT in unresectable locally advanced NSCLC patients with EGFR or ALK mutation demonstrates comparable clinical outcomes to those with wild-type EGFR/ALK when PD-L1 expression is present.

Association of PD-L1 immunoexpression with tumor grade in colorectal adenocarcinoma

Globally, colorectal cancer (CRC) is the primary cause of cancer-related deaths, and in emerging countries, its prevalence is continuously increasing. With all the advancements in surgery and treatment, the outlook for CRC patients is still not good. Even with the use of standard prognostic markers, there are presently no effective prognostic techniques for colorectal cancer. The long-term survival of many malignancies has been significantly enhanced by immune checkpoint blockades (ICB), suggesting that the immune checkpoint mechanism is crucial in inhibiting tumor-specific immune responses in the tumor microenvironment. By inhibiting T effector cell activity, the "PD-1 (programmed cell death-1)"/PD-L1 (programmed cell death-ligand 1) axis contributes significantly to immune suppression control and allows tumor cells to evade the host's anti-tumor immune surveillance. While early study suggested that immunotherapy was not relevant for patients with colorectal cancer, more recent studies have demonstrated that immunotherapy was beneficial for a certain subset of patients. This suggests that the prognosis prediction of colorectal cancer may benefit from a thorough evaluation of the local immune response. This study set out to assess the association between PD-L1 immunoexpression and tumor grade in CRC. : This was a cross-sectional observational study. Paraffin blocks of total 64 cases were selected from the patients who were diagnosed as adenocarcinoma from resected samples received in the department of pathology at BSMMU from July 2021 to June 2023. Immuno-histochemical staining for PD-L1 was performed using 28-8 clone along with appropriate positive control. In this study, PD-L1 immuno-expression was found in 14(21.9%) out of 64 cases. However, no expression was found in rest of the 50 (78.1%) cases. This study showed association of PD-L1 expression with high grade (Grade-3) tumors. : Evaluation of expression of PD-L1 may emerge as a new marker and target for the immunotherapy of colorectal cancer.

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).

The Clinicopathological and Prognostic Significance of the Expression of PD-L1 and MET Genes in Breast Cancer: Potential Therapeutic Targets.

The heterogeneity of breast cancer requires exploring novel prognostic biomarkers as well as therapeutic targets for the treatment of the disease. The METABRIC dataset was used to describe the gene expression of the programmed death-ligand 1 (PD-L1) and the hepatocyte growth factor receptor (MET) and their association with the tumor clinicopathologic characteristics and overall survival in breast cancer. The expression of the PD-L1 and MET genes correlated positively with the Nottingham Prognostic Index (NPI) (p=0.003 and p < 0.001, respectively). The expression of the two genes correlated inversely with luminal A and luminal B tumors (r= - 0.089, p= 0.021 and r= - 0.116, p= 0.013, respectively). The PD-L1 mRNA levels were significantly higher in hormone receptor-negative and HER2-positive tumors. MET mRNA expression levels were significantly higher in hormone receptor-negative, HER2-enriched, and non-luminal breast cancers. The PD-L1/MET double-high expression was associated with younger age of patients at diagnosis, higher NPI scores, larger tumors, advanced stage, high-grade, hormone receptor-negativity, HER2-positivity, and non-luminal tumors. None of the genes or their double expression status was significantly associated with overall survival in this analysis. The expression of the PD-L1 and MET genes is remarkably associated with worse tumor clinicopathologic features and poor prognosis in patients with breast cancer. Further investigations using combination drug regimens targeting PD-L1 and MET are important, particularly in breast tumors expressing high levels of both proteins.

PD-L1+ Lymphocytes Are Associated with CD4+, Foxp3+CD4+, IL17+CD4+ T Cells and Subtypes of Macrophages in Resected Early-Stage Non-Small Cell Lung Cancer.

The non-canonical PD-L1 pathway revealed that programmed-death ligand 1 (PD-L1) expression in immune cells also plays a crucial role in immune response. Moreover, immune cell distribution in a tumour microenvironment (TME) is pivotal for tumour genesis. However, the results remain controversial and further research is needed. Distribution of PD-L1-positive (PD-L1+) tumour-infiltrating lymphocytes in the context of TME was assessed in 72 archival I-III stage surgically resected NSCLC tumour specimens. Predominant PD-L1+ lymphocyte distribution in the tumour stroma, compared to islets, was found (p = 0.01). Higher PD-L1+ lymphocyte infiltration was detected in smokers due to their predominance in the stroma. High PD-L1+ lymphocyte infiltration in tumour stroma was more common in tumours with higher CD4+ T cell infiltration in islets and stroma, Foxp3+CD4+ T cell infiltration in islets and lover M1 macrophage infiltration in the stroma (p = 0.034, p = 0.034, p = 0.005 and p = 0.034 respectively). Meanwhile, high PD-L1+ lymphocyte infiltration in islets was predominantly found in tumours with high levels of IL-17A+CD4+ T cells in islets and Foxp3+CD4+ T cells in islets and stroma (p = 0.032, p = 0.009 and p = 0.034, respectively). Significant correlations between PD-L1+ lymphocytes and tumour-infiltrating CD4+, Foxp3+CD4+, IL-17A+CD4+ T cells and M2 macrophages were found. An analysis of the tumour-immune phenotype revealed a significant association between PD-L1 expression and IL17+CD4+ and Foxp3+CD4+ immune phenotypes. PD-L1+ lymphocytes are associated with the distribution of CD4+, Foxp3+CD4+, IL17A+CD4+ T cells, M1 and M2 macrophages in TME of resected NSCLC.

Peptide-directed interference of PD-1/PD-L1 binding increases B lymphocyte function after infectious bursal disease viral infection

Programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) binding contributes to immune evasion mechanisms responsible for B lymphocyte exhaustion and apoptosis. This facilitates immunosuppression in chronic viral infections, including infectious bursal disease virus (IBDV). Our previous study showed that PD-1 and PD-L1 expression increases in the peripheral blood mononuclear cells of chickens infected with IBDV. However, due to their high production costs and immune-related adverse events, monoclonal antibodies targeting PD-1 or PD-L1 are unsuitable therapeutic agents. Thus, in the current study, we designed peptides with optimized binding sites for PD-1 and investigated their ability to disrupt PD-1/PD-L1 binding and restore B lymphocyte function in vitro. The peptide gCK-16 exhibited a high affinity for PD-1 (KD: 3.37 nM) and effectively inhibited the PD-1/PD-L1 interaction in vitro. Moreover, gCK-16 significantly enhanced B lymphocyte proliferation. Remarkably, gCK-16 treatment abrogated the IBDV-induced upregulation of PD-1/PD-L1, NF-κB activation, and B lymphocyte apoptosis. Additionally, IBDV infection attenuated PI3K/AKT pathway activation in B lymphocytes, while gCK-16 treatment increased immunoglobulin M (IgM) production in IBDV-infected B lymphocytes. Together, these results demonstrate that gCK-16 treatment can potentially enhance B lymphocyte function against IBDV infection, guiding the development of vaccine adjuvants to effectively prevent IBDV-induced avian immunosuppression.

Prognostic Significance of Programmed Cell Death-Ligand 1 Expression in Tobacco Associated Oral Squamous Cell Carcinoma: An Immunohistochemical Based Cross-Sectional Study.

Advancements in immuno-oncology have dramatically transformed cancer treatment. Immunotherapy, targeting immune check point proteins, notably Programmed cell death ligand 1 (PD-L1) and its receptor Programmed Cell Death-1 (PD-1) which modulate the activity of immune response in Head and Neck squamous cell carcinomas (HNSCC), is an area of much research. The immunohistochemical expression of PD-L1 in cancer cells has been proposed as a predictive biomarker for selecting candidates for immunotherapy. Thus, the present study was undertaken to study the expression of PD-L1 in the primary tumour cells and evaluate its correlation with various clinicopathological parameters and prognosis in tobacco associated oral squamous cell carcinomas (OSCC). Expression of PD-L1 was investigated in 75 surgically resected cases of OSCC by immunohistochemistry and its association with different clinicopathological features and prognosis was analysed. PD-L1 protein was detected in 68% (51 cases) of cases. Tumour stage (p = 0.04), lymph node (LN) metastasis (p < 0.01) and moderate to marked tumour infiltrating lymphocytes (TILs) (p < 0.05), significantly correlated with the PD-L1 expression in the primary tumour. PD-L1 expression did not show a significant association with overall survival (OS) rate, however, patients with positive PD-L1 expression showed a poorer survival rate. Patients exhibiting nodal positivity had the worst prognosis (p < 0.005). These data demonstrated a significant association of ≥ 5% PD-L1 expression in the primary tumour and the presence of LN metastasis, moderate to marked TILs and advancing tumour stage, thus, making it a plausible immunotherapeutic target molecule in OSCC patients.

Investigation of Programmed Death Ligand-1 as a New Prognostic Biomarker in Pancreatic Cancer Patients.

Pancreatic cancer is one of the most lethal and fast-growing cancers with a poor prognosis. Herein, we report the expression of programmed death ligand 1 (PD-L1) as a new prognostic biomarker in pancreatic cancer progression analysis at the clinical level. Immunohistochemistry was performed on 86 clinically proven cases of pancreatic cancer tissue microarrays (TMAs) using anti-PD-L1 antibodies. Histoscore was done, and a variety of cutoffs were identified for analyses of the results. The chi-square test and Kaplan-Meier method were used to find the association between pancreatic cancer and various clinicopathological variables and the overall survival of the patients. PD-L1 expression was associated with histological grade and recurrence of the disease for epithelial and stromal staining at 10 histoscores. In addition, PD-L1 expression was strongly associated with lymph node involvement at the stromal 20 histoscore. The tumor stage of pancreatic cancer had an association with PD-L1 expression with epithelial and stromal 20 histoscores for all comparisons. At a stromal 20 histoscore, overall survival in high-low expression of PD-L1 was 7-19 months, and at a nuclear/cytoplasmic 10 histoscore, it was 9-28 months (p = 0.0001), respectively. Overall, PD-L1 overexpression in subcellular compartments was associated with disease aggression phenotypes and poor patient survival. Overexpression of PD-L1 was directly linked to pancreatic cancer progression and a poor survival rate. Therefore, PD-L1 may be used as a prognostic biomarker in the diagnosis, treatment, and management of pancreatic cancer patients.