Programmed Death-ligand 1 Levels Research Articles

Cost-effectiveness of cemiplimab plus chemotherapy vs pembrolizumab plus chemotherapy as first-line treatment for advanced non-small cell lung cancer.

In 2022, the US Food and Drug Administration approved cemiplimab in combination with chemotherapy (CCT) as a first-line treatment for advanced non-small cell lung cancer (aNSCLC). However, whether CCT presents a cost-effective alternative to the previously preferred first-line treatment, pembrolizumab plus chemotherapy (PCT), remains uncertain. To evaluate the cost-effectiveness of CCT vs PCT as the first-line treatment for aNSCLC from a US health care payer perspective. A 3-state partitioned survival model with a 10-year horizon was constructed. Clinical data were derived from the EMPOWER-Lung 3, KEYNOTE-407, and KEYNOTE-189 trials. Costs and quality of life were obtained from published 2024 US list prices and literature. The cost, quality-adjusted life-years (QALYs) gained, and incremental cost-effectiveness ratio (ICER) were calculated. All outcomes were discounted at a rate of 3% per year. Scenario analyses, deterministic and probabilistic sensitivity analyses, and subgroup analyses were performed for patients with different programmed death ligand 1 (PD-L1) levels. In the base-case analysis, the total cost of PCT was $207,926 with 1.609 QALYs, whereas CCT had a total cost of $175,247 with 1.657 QALYs. Results from the scenario analyses were consistent with the base-case analysis, indicating that CCT was a dominant treatment strategy over PCT (ICER =-$675,304 per QALY). The cost of pembrolizumab highly impacted the ICER. At a willingness-to-pay threshold of $150,000 per QALY, CCT would be accepted as a cost-effective option 96.9% of the time. In subgroup analyses, CCT remained a dominant alternative to PCT for patients with PD-L1 levels of at least 50% and 1%-49%. This cost-effectiveness analysis suggests that CCT is a dominant first-line treatment option for aNSCLC with PD-L1 levels of at least 1% compared with PCT.

PD-L1 peptides in cancer immunoimaging and immunotherapy.

The interaction between programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) constitutes a critical immune checkpoint pathway that leads to immune tolerance in cancer cells and impacts antitumor treatment. Monoclonal antibody blockade of the PD-L1 immunoinhibitory pathway has demonstrated significant and lasting clinical antitumor responses. Furthermore, PD-L1 serves as an important biomarker for predicting the effectiveness of immune checkpoint inhibitors (ICIs). To date, numerous studies based on monoclonal antibodies have been carried out to detect the expression levels of PD-L1 and predict the antitumor effectiveness of PD-L1 ICIs. However, due to the deficiencies of monoclonal antibodies, researches of PD-L1 peptides have received increasing attention. PD-L1 peptides present promising candidates due to their advantages, including reduced manufacturing costs, enhanced stability, decreased immunogenicity, faster clearance and improved tumor or organ penetration, thereby offering broad application prospects in cancer immunoimaging and immunotherapy. In this review, we analyze the existing evidence on PD-L1 peptides in cancer immunoimaging and immunotherapy. First, the design techniques of different types of PD-L1 targeting peptides and their strengths and weaknesses are briefly introduced. Second, the recent advancements in immunoimaging and the development trends in immunotherapy are summarized. Finally, the existing challenges and future directions in this field are comprehensively deliberated.

Jumonji domain-containing protein 6 promotes gastric cancer progression: Modulating immune evasion through autophagy and oxidative stress pathways

Objective: Immune response is crucial in the development of gastric cancer (GC), and Jumonji domain-containing protein 6 (JMJD6) plays an important role in mediating GC cell behavior. This study aims to elucidate the mechanisms through which JMJD6 affects autophagy and immune evasion in GC cells. Material and Methods: Immunocytochemistry was employed to assess JMJD6 and programmed death-ligand 1 (PD-L1) levels in gastric cancer cell line (MKN-45) and gastric epithelial cell line cells. MKN-45 cells with JMJD6 knockdown and overexpression were generated. The effect of JMJD6 on MKN-45 cells was evaluated using cell counting kit-8 assay, cellular fluorescence staining, and Transwell assays. Western blot analysis and immunofluorescence techniques were employed to investigate the regulation of autophagy by JMJD6. Reactive oxygen species (ROS) levels were evaluated by applying ROS fluorescence staining. Meanwhile, the protein and gene expression levels of molecules related to antioxidant stress responses were assessed through immunofluorescence assays and quantitative real-time polymerase chain reactions, respectively. Results: The expression levels of JMJD6 and PD-L1 were elevated in GC cells (P < 0.001). JMJD6 overexpression enhanced MKN-45 cell migration, invasion, and colony formation in vitro (P < 0.001). In MKN-45 cells, the epithelial-mesenchymal transition was promoted by JMJD6 upregulation but was notably inhibited by JMJD6 knockdown (P < 0.001). JMJD6 overexpression increased the expression levels of Sequestosome 1, Microtubule-associated protein 1A/1B-light chain 3 (LC3)II/LC3I, and PD-L1 in MKN-45 cells, and autophagy activation further elevated PD-L1 levels (P < 0.001). In addition, JMJD6 overexpression reduced ROS production and increased the expression of molecules related to antioxidant stress response, with the reverse effects observed on JMJD6 knockdown (P < 0.001). Conclusion: JMJD6 notably facilitates GC progression and immune evasion by modulating autophagy and oxidative stress pathways.

Efficacy and Safety of Immunotherapy Combined with Anlotinib as FirstLine Treatment in Older NSCLC Patients with PD-L1 Expression

Non-small cell lung cancer (NSCLC) predominantly affects older adults; these patients have significant comorbidities, making them unsuitable for chemotherapy. This study aimed to evaluate the efficacy and safety of immune checkpoint inhibitor (ICI) along with anlotinib combination therapy as a first-line treatment in older NSCLC patients with programmed death ligand-1(PD-L1) expression＜50%. We conducted a retrospective observational study including 73 patients with advanced NSCLC treated at Nanjing Brain Hospital. All patients were aged 75 years or older and received first-line systemic therapy with a combination of PD-1 inhibitors and anlotinib. Clinical data were obtained from electronic medical records and analyzed through Kaplan-Meier estimates and Cox proportional hazards models to assess progression-free survival (PFS), overall survival (OS), and the influence of different variables. The patients had a median age of 80 years. The median PFS was 9.8 months (95% CI: 7.9-11.7), and the median OS was 19.5 months (95% CI: 17.3-21.7). PD-L1 tumor proportion score (TPS) <1% (χ2=10.263, P=0.001) and absence of treatment-induced hypertension (χ2=12.804, P<0.001) were identified as independent risk factors for poor PFS. Advanced disease stage (χ2=11.900, P=0.001), PD-L1 TPS <1% (χ2=6.643, P=0.010), and having two or more chronic comorbidities (χ2=9.011, P=0.003) were independent risk factors for poor OS. Treatment-related hypertension was observed in 25% of patients and was associated with better PFS. ICI-anlotinib combination therapy showed promising efficacy and an acceptable safety profile in older NSCLC patients. Future studies involving larger populations are necessary to validate these findings and determine the potential of PD-L1 levels as a biomarker for treatment stratification.

A responsive cocktail nano-strategy breaking the immune excluded state enhances immunotherapy for triple negative breast cancer.

The exclusion of immune cells from the tumor can limit the effectiveness of immunotherapy in triple negative breast cancer (TNBC). The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway plays a crucial role in priming adaptive anti-tumor immunity through the production of type I interferons (IFNs), facilitating the maturation of dendritic cells (DCs) and the function of T cells. Although the increased expression of programmed death-ligand 1 (PD-L1) upon STING activation is favorable for amplifying the efficacy of immune checkpoint inhibitors (ICIs) and realizing combination therapy, the penetration barrier remains a major obstacle. Herein, we fabricated a smart-responsive nanosystem (B&V@ZB-MCL) by integrating the extracellular matrix (ECM)-degrading drug losartan with a STING agonist (Vadimezan, abbreviated to Vad) and a PD-L1 inhibitor (BMS-1). Losartan was first released in the acidic tumor microenvironment to overcome the physical barrier, enhancing the penetration of immunotherapeutic components. Under the triggering of 1O2 generated by a photosensitizer (Ce6), the reactive oxygen species (ROS)-sensitive degradation of the nanocore ensured the site-directed release of Vad and BMS-1. The released Vad and damaged tumor DNA activated immune responses through the cGAS-STING pathway, while the elevated expression level of PD-L1 promoted the anti-tumor effect of BMS-1. Significant degradation of collagen fibers, restoration of immune effector cells, and lower tumor volume were observed in this integrated triple drug sequential therapy, which provides a promising prospect for TNBC treatment.

CircENTPD7 affects the immune escape of non‑small cell lung cancer cells by modulating the IGF2BP2/PD‑L1 axis.

Programmed death ligand 1 (PD-L1), an important immune checkpoint molecule, is abnormally activated in non-small cell lung cancer (NSCLC), which can interact with programmed death 1 to aid cancer cells in evading immune surveillance. Furthermore, tumor driver genes may be involved in the occurrence and development of NSCLC and have a potential role in PD-L1-mediated immune escape mechanisms. Therefore, the present study aimed to assess the behavioral and regulatory mechanisms by which circular RNA ENTPD7 (circENTPD7; hsa_circ_0019421) induces an immune response in the progression of NSCLC cells. In brief, circENTPD7, insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and PD-L1 expression were assessed using reverse transcription-quantitative PCR, and IGF2BP2 and PD-L1 protein expression levels were evaluated using western blotting. Subsequently, the proliferation, migration, invasion and immune escape of NSCLC cells were assessed using a Cell Counting Kit-8 assay, Transwell assay, T cell co-culture assay, FITC ester assay, flow cytometry and ELISA. The experimental results revealed that circENTPD7, IGF2BP2 and PD-L1 levels were significantly elevated in NSCLC cells. CircENTPD7 knockdown suppressed the malignant phenotype of NSCLC cells, whereas overexpression of IGF2BP2 counteracted these effects, indicating that circENTPD7 contributed to the proliferation and metastasis of NSCLC cells by upregulating IGF2BP2. Furthermore, overexpression of IGF2BP2 accelerated the proliferation, metastasis and immune escape processes of NSCLC cells by upregulating PD-L1. Collectively, the results indicate that circENTPD7 contributes to the malignant progression of NSCLC cells by modulating the IGF2BP2/PD-L1 axis-mediated immune escape.

Expression and clinical significance of programmed death ligand-1 evaluated by 22C3 antibody in pleural effusion metastatic non-small-cell lung cancer.

Programmed death ligand-1 (PD-L1) is involved in tumor immune escape and is an important target molecule for the immunotherapy of non-small-cell lung cancer (NSCLC). The expression of PD-L1 affects NSCLC invasion, metastasis, and patient survival. This study aims to explore the levels of PD-L1, as identified by the 22C3 antibody, in the malignant pleural effusion of patients suffering from advanced NSCLC, and to determine its clinical implications. A two-step immunohistochemical EnVision assay was used to evaluate the expression of PD-L1 by the 22C3 antibody in 149 malignant pleural fluid cell wax clots of NSCLC. The relationship between PDL1 expression and clinicopathological characteristics, anaplastic lymphoma kinase (ALK) expression, epidermal growth factor receptor (EGFR) mutation, and overall survival (OS) time of patients with NSCLC was analyzed. Positive expression of PD-L1 in malignant pleural fluid of NSCLC was observed as follows: Positive (<1%: 11.4%), positive (1-49%: 19.5%), and positive (≥50%: 11.4%), with a total positive rate of 42.3%. There was a significant association between PD-L1-positive expression and factors such as tumor differentiation, lymph node metastasis, and metastasis to other organs (P < 0.05). Furthermore, PD-L1 expression showed a positive correlation with ALK expression (rs = 11.49, P < 0.05) but did not correlate with EGFR mutations (rs = 0.004, P > 0.05). Significant differences in median OS were observed between patients exhibiting positive PD-L1 expression and those without, according to survival follow-up data (P < 0.05). Immunohistochemical detection of PD-L1 expression in malignant pleural fluid of advanced NSCLC provides a basis for clinical tumor immunotherapy. Immunohistochemical detection of PD-L1 expression in malignant pleural fluid of advanced NSCLC is minimally invasive, simple, and fast, particularly for metastatic NSCLC where malignant pleural fluid is the first symptom, offering significant clinical application value.

Study on the mechanism of liver cancer immune escape mediated by MINDY1 through regulation of PD-L1 ubiquitination level.

The novel deubiquitinase enzyme, motif interacting with ubiquitin-containing novel DUB family-1 (MINDY1), is highly expressed in liver cancer tissues and plays a crucial role in maintaining the stemness of liver cancer cells. Programmed death ligand-1 (PD-L1) is an immunosuppressive molecule overexpressed by tumour cells. The potential role of MINDY1 in inhibiting the stemness of liver cancer cells by deubiquitinating PD-L1 has not yet been reported. To investigate the mechanism by which MINDY1 mediates immune escape in liver cancer through the regulation of PD-L1 ubiquitination, we examined the expression levels of MINDY1 and PD-L1 in liver cancer and adjacent tissues from 50 hepatocellular carcinoma (HCC) patients using protein imprinting and immunohistochemistry. We analyzed the relationship between the expression levels of MINDY1 and PD-L1 in liver cancer tissues and their correlation with the 5-year tumor-free survival rates of patients. Subsequently, MINDY1 expression was knocked down in Huh7 cells using small interfering RNA (siRNA) interference or upregulated through transfection with a MINDY1 overexpression plasmid. The effects of MINDY1 knockdown or overexpression on the proliferation, apoptosis, migration, and invasion of HCC cells, as well as the regulation of PD-L1 binding and ubiquitination, were assessed. The 5-year tumor-free survival rates were significantly lower in both the high MINDY1 expression group and the high PD-L1 expression group (χ2 = 4.919 and 13.158, respectively).A significant difference in survival was observed between the high and low MINDY1 expression groups (χ2= 27.415). MINDY1 was found to directly interact with PD-L1, with MINDY1 gene knockdown promoting PD-L1 ubiquitination and MINDY1 overexpression inhibiting PD-L1 ubiquitination. All comparisons yielded statistically significant results (P < 0.05). In conclusion, MINDY1 inhibits the malignant progression of liver cancer by inhibiting PD-L1 ubiquitination and mediating immune escape.

Sea Hare Hydrolysate Reduces PD-L1 Levels in Cancer Cells and Mitigates Rheumatoid Arthritis Ina Collagen-Induced Arthritis Mouse Model.

Our previous study highlighted the anticancer potential of sea hare hydrolysate (SHH), particularly its role in regulating macrophage polarization and inducing pyroptotic death in lung cancer cells through the inhibition of signal transducer and activator of transcription 3 (STAT3). These findings prompted us to investigate additional features of immune-oncology (I-O) agents or adjuvants, such as programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibition and their association with rheumatoid arthritis (RA) risk, to explore the potential of SHH as an I-O agent or adjuvant. In this study, we investigated the effects of SHH on PD-L1 levels in various cancer cell types and assessed its effectiveness in treating RA, a common side effect of I-O agents. Our results showed a marked reduction in PD-L1 levels in multiple cancer cell lines and decreased PD-1 and PD-L1 levels in tumor-associated macrophages. In a mouse model with collagen-induced arthritis (CIA), SHH exhibited anti-inflammatory effects comparable to methotrexate (MTX), a first-line treatment for RA. Both the SHH and MTX groups had significantly lower arthritis scores and paw thickness compared to the CIA group. Additionally, SHH or MTX treatment effectively reduced elevated levels of anticollagen type II (CII) antibodies and proinflammatory cytokines (IL-1β, IL-6, and TNF-α). Histopathological analysis revealed that SHH and MTX treatments notably mitigated arthritic inflammation, synovial hyperplasia, and loss of articular cartilage and bone. Micro-CT scans showed reduced articular destruction in the SHH and MTX groups. These findings indicate that SHH treatment decreases PD-L1 levels in cancer cells and reduces the severity of CIA by exerting anti-inflammatory effects. Therefore, SHH holds promise as an I-O agent without side effects such as exacerbation of RA.

Biomarker analyses from the phase III randomized CLEAR trial: lenvatinib plus pembrolizumab versus sunitinib in advanced renal cell carcinoma.

In CLEAR, lenvatinib+ pembrolizumab (L+ P) significantly improved efficacy versus sunitinib in first-line treatment of patients with advanced renal cell carcinoma (aRCC). We report results from CLEAR biomarker analyses. Programmed death-ligand 1 (PD-L1) immunohistochemistry (IHC) and next-generation sequencing assays (whole exome sequencing/RNA sequencing) were carried out on archival tumor specimens. For IHC-derived/RNA sequencing analyses, a continuous analysis was carried out adjusting by Karnofsky performance status (KPS) score for: PD-L1 combined positive score (CPS) versus best overall response (BOR)/progression-free survival (PFS); and each gene signature score [T-cell inflamed gene expression profile (TcellinfGEP)/non-TcellinfGEP signatures including proliferation and angiogenesis] versus BOR/PFS. Association between mutation status of RCC driver genes and PFS were analyzed for genes for which ≥20 patients per arm had oncogenic alterations. Association of molecular subtypes with outcome was evaluated with baseline KPS adjustments. The set of biomarkers evaluated and statistical significance criteria for PD-L1 CPS, gene signature scores, and molecular subtypes were prespecified. Within-arm analyses using continuous values showed no association between PD-L1 levels and BOR/PFS for either treatment. PFS hazard ratios between arms were similar regardless of the mutant or wild-type subgroups of RCC driver genes (VHL, PBRM1, SETD2, BAP1, KDM5C). No associations between PFS and gene signature scores were observed for L+ P. With sunitinib, high proliferation and MYC signature scores showed shorter PFS; high angiogenesis and microvessel density signature scores showed longer PFS. Six new molecular subtypes were defined. Tumors of patients with favorable/intermediate risk were enriched in angiogenesis and angiogenesis/stromal clusters; those with poor risk were enriched in proliferative and unclassified (low-TcellinfGEP/low-angiogenesis/low-proliferation) clusters. No association between molecular subtypes and PFS for L+ P/sunitinib was observed (after adjustment for KPS and gene signatures that were individually associated with PFS). Improvements in objective response rate and PFS for L+ P versus sunitinib in aRCC were observed consistently across a range of biomarker subgroups defined using RCC driver mutations, PD-L1, gene expression signatures, and molecular subtypes.

LKB1 dictates sensitivity to immunotherapy through Skp2-mediated ubiquitination of PD-L1 protein in non-small cell lung cancer

BackgroundLoss-of-function mutations of liver kinase B (LKB1, also termed as STK11 (serine/threonine kinase 11)) are frequently detected in patients with non-small cell lung cancer (NSCLC). The LKB1 mutant NSCLC was...

LRP1B Suppresses Immunotherapy Efficacy in Lung Adenocarcinoma by Preventing Ferroptosis.

Immune biomarkers for non-small-cell lung cancer (NSCLC) are programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB). However, they cannot accurately predict the effectiveness of immunotherapy. Identifying appropriate biomarkers that can differentiate between beneficiary groups is imperative. We identified lipoprotein receptor-related protein 1B (LRP1B) mutation as a potential biomarker for immunotherapy by analyzing clinical data, combined with bioinformatics analysis. The effects of LRP1B on ferroptosis were assessed using qRT-PCR, Western blotting, CCK-8 assay, and flow cytometry. The potential mechanism underlying the regulation of ferroptosis by LRP1B was elucidated using qRT-PCR, Western blotting, ChIP, and dual-luciferase reporter gene assays. Through the collection and analysis of clinical data, we had established that LRP1B mutations are closely associated with immunotherapy. Bioinformatics analysis revealed significant differences in the expression levels of PD-L1 and TMB between patients with LRP1B mutation and wild-type patients in lung adenocarcinoma (LUAD). Furthermore, we observed that patients with LRP1B mutation in LUAD had significantly higher levels of tumor-infiltrating lymphocytes (TILs) than wild-type patients. In addition, we found that patients with LRP1B mutation in LUAD had significantly prolonged progression-free survival (PFS) compared to wild-type patients. However, the differences of PD-L1 expression, TILs, and PFS were not observed in patients with LRP1B mutation in lung squamous cell carcinoma (LUSC). These findings provided strong evidence that LRP1B mutation was a potential biomarker for immunotherapy in LUAD. Moreover, our invivo experiments indicated that knockdown of LRP1B enhanced the efficacy of mPD-1, and mechanistic studies revealed that LRP1B regulated the sensitivity of cells to ferroptosis by modulating the expression of SLC7A11 through altering the phosphorylation level of STAT3. Further analysis revealed that LRP1B knockdown promoted immunotherapy invivo. Our results confirmed that LRP1B affected the efficacy of immunotherapy by modulating the sensitivity of NSCLC cells to ferroptosis. LRP1B mutations represent a highly promising immunotherapeutic biomarker for NSCLC.

PTEN loss in glioma cell lines leads to increased extracellular vesicle biogenesis and PD-L1 cargo in a PI3K-dependent manner.

Phosphatase and Tensin Homolog (PTEN) is one of the most frequently lost tumor suppressors in cancer and the predominant negative regulator of the PI3K-AKT signaling axis. A growing body of evidence has highlighted the loss of PTEN with immuno-modulatory functions including the upregulation of the programmed death ligand-1 (PD-L1), an altered tumor-derived secretome that drives an immunosuppressive tumor immune microenvironment and resistance to certain immunotherapies. Given their roles in immunosuppression and tumor growth, we examined whether the loss of PTEN would impact the biogenesis, cargo, and function of extracellular vesicles (EVs) in the context of the anti-tumor associated cytokine interferon-γ. Through genetic and pharmacological approaches, we show that total cellular expression of PD-L1 is regulated by JAK/STAT signaling, not PI3K signaling. Instead, we observe that PTEN loss specifically upregulates cell surface levels of PD-L1 and enhances the biogenesis of EVs enriched with PD-L1 in a PI3K-dependent manner. We demonstrate that because of these changes, EVs derived from glioma cells lacking PTEN have a greater ability to suppress T cell receptor signaling. Taken together, these findings provide important new insights into how the loss of PTEN can contribute to an immunosuppressive tumor immune microenvironment, facilitate immune evasion, and highlight a novel role for PI3K signaling in the regulation of EV biogenesis and the cargo they contain.

Beta cell extracellular vesicle PD-L1 as a novel regulator of CD8+ T cell activity and biomarker during the evolution of type 1 diabetes.

Surviving beta cells in type 1 diabetes respond to inflammation by upregulating programmed death-ligand 1 (PD-L1) to engage immune cell programmed death protein 1 (PD-1) and limit destruction by self-reactive immune cells. Extracellular vesicles (EVs) and their cargo can serve as biomarkers of beta cell health and contribute to islet intercellular communication. We hypothesised that the inflammatory milieu of type 1 diabetes increases PD-L1 in beta cell EV cargo and that EV PD-L1 may protect beta cells against immune-mediated cell death. Beta cell lines and human islets were treated with proinflammatory cytokines to model the proinflammatory type 1 diabetes microenvironment. EVs were isolated using ultracentrifugation or size exclusion chromatography and analysed via immunoblot, flow cytometry and ELISA. EV PD-L1 binding to PD-1 was assessed using a competitive binding assay and in vitro functional assays testing the ability of EV PD-L1 to inhibit NOD CD8+ T cells. Plasma EV and soluble PD-L1 were assayed in the plasma of islet autoantibody-positive (Ab+) individuals or individuals with recent-onset type 1 diabetes and compared with levels in non-diabetic control individuals. PD-L1 protein co-localised with tetraspanin-associated proteins intracellularly and was detected on the surface of beta cell EVs. Treatment with IFN-α or IFN-γ for 24 h induced a twofold increase in EV PD-L1 cargo without a corresponding increase in the number of EVs. IFN exposure predominantly increased PD-L1 expression on the surface of beta cell EVs and beta cell EV PD-L1 showed a dose-dependent capacity to bind PD-1. Functional experiments demonstrated specific effects of beta cell EV PD-L1 to suppress proliferation and cytotoxicity of murine CD8+ T cells. Plasma EV PD-L1 levels were increased in Ab+individuals, particularly in those positive for a single autoantibody. Additionally, in Ab+ individuals or those who had type 1 diabetes, but not in control individuals, plasma EV PD-L1 positively correlated with circulating C-peptide, suggesting that higher EV PD-L1 could be protective for residual beta cell function. IFN exposure increases PD-L1 on the beta cell EV surface. Beta cell EV PD-L1 binds PD1 and inhibits CD8+ T cell proliferation and cytotoxicity. Circulating EV PD-L1 is higher in Ab+ individuals than in control individuals. Circulating EV PD-L1 levels correlate with residual C-peptide at different stages in type 1 diabetes progression. These findings suggest that EV PD-L1 could contribute to heterogeneity in type 1 diabetes progression and residual beta cell function and raise the possibility that EV PD-L1 could be exploited as a means to inhibit immune-mediated beta cell death.

The role of PD-1/PD-L1 pathway in ulcerative colitis and changes following tonsil-derived mesenchymal stem cells treatment.

The programmed death 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway has not been fully evaluated in inflammatory bowel disease. We evaluated PD-1/PD-L1 levels in patients with ulcerative colitis (UC) and their significance in tonsil-derived mesenchymal stem cells (TMSCs) treatment. Using acute and chronic murine colitis model, we measured the PD-1 and PD-L1 levels in inflamed colonic tissues pre- and post-treatment with TMSCs. We also measured PD-1 and PD-L1 levels in colonic tissues from UC patients, compared to normal controls. In the analysis using human colonic tissues, a significant increase in the levels of PD-1 and PD-L1 was observed in the colonic mucosa of patients with UC compared with normal controls (p < 0.001 and p = 0.005, respectively). When comparing the maximal disease extent, PD-L1 levels were highest in patients with proctitis (38.5 ± 46.7), followed by left-side colitis (17.5 ± 23.1) and extensive colitis (5.2 ± 8.2) (p < 0.001). In the chronic colitis model, the level of PD-L1 was decreased (p = 0.040) and the level of PD-1 increased more than in normal controls (p = 0.047). After treatment with TMSC, significant improvements were observed in body weight, disease activity index, and colon length recovery. Additionally, the levels of PD-1 and PD-L1 were recovered; PD-L1 significantly increased (p = 0.031), while the level of PD-1 decreased (p = 0.310). The altered expression of PD-1 and PD-L1 in colonic mucosa may be a possible mechanism of UC, and T-MSC-derived PD-L1 could help suppress colitis.

IL-4 Downregulates PD-L1 Level Via SOCS1 Upregulation-Induced JNK Deactivation to Enhance Antitumor Immunity in In Vitro Colorectal Cancer.

Interleukin-4 (IL-4) controls cell growth and immune system regulation in tumorigenesis and can inhibit the growth of colon cancer cell lines, but the possible mechanism is unclear. In this study, we investigated the possible mechanism of IL-4 in colorectal cancer (CRC) through in vitro experiments. CRC cells received treatment with IL-4 (50 ng/mL), investigating the suppressor of cytokine signaling 1 (SOCS1)-related mechanism underlying the role of IL-4 in the progression and immunosuppression of CRC. The malignant processes of CRC cells and CD8+T cell-mediated immune response in CRC cells were determined by CCK-8, Transwell, wound healing, and flow cytometry assays. Programmed death ligand 1 (PD-L1), SOCS1 expressions, and c-Jun N-terminal kinase (JNK) activation in CRC cells were analyzed by quantitative reverse transcription polymerase chain reaction and/or Western blot. IL-4 repressed the malignant processes, yet promoted the apoptosis of CRC cells. Besides, IL-4 downregulated PD-L1 level, upregulated SOCS1 level, and restrained JNK activation in CRC cells, while enhancing CRC cell-killing effect of CD8+T cells. IL-4-induced effects on the aforementioned malignant processes of CRC cells and the killing effect of CD8+T cells toward CRC cells were all reversed when SOCS1 was knocked down in the CRC cells. IL-4 downregulates PD-L1 level via SOCS1 upregulation-induced JNK deactivation to enhance antitumor immunity in in vitro CRC. The study provides a theoretical basis for the clinical application of IL-4 in antitumor immunity in CRC.

B7-H3 is widely expressed in soft tissue sarcomas

PurposeTargeted therapy development in soft tissue sarcoma (STS) has been burdened by the heterogeneity of this group of rare tumors. B7 homolog 3 protein (B7-H3) is a molecule in the same family as programmed death-ligand 1 (PD-L1). It has limited expression in noncancerous tissues and is overexpressed in many cancers, making it an attractive target for cancer therapy, and clinical trials targeting B7-H3 are actively underway. While available data demonstrate high expression levels of B7-H3 in individual sarcoma subtypes, its expression patterns across STS subtypes are not well described. The purpose of this study was to characterize the expression patterns of B7-H3 in STS.Patients and methodsThis retrospective analysis evaluated STS tumor specimens from patients with a variety of different subtypes. Specimens were evaluated by immunohistochemistry (IHC) for expression and staining pattern of B7-H3 both in tumors and in associated vasculature.ResultsSpecimens from 153 sarcoma patients included 15 different STS subtypes. B7-H3 was broadly expressed in 97% of samples (95% CI 0.93–0.99) and 69.2% demonstrated high levels of B7-H3 expression (95% CI 0.61–0.76). No significant association between B7-H3 positivity or expression level and prior treatment(s), tumor size, tumor grade, or patient age. B7-H3 positivity in vessels was found in 94.7% (145/153) of samples. In tumors that had been previously assessed for PD-L1 and PD-1, there was no correlation between B7-H3 positivity or expression and the positivity or expression level of PD-L1 or PD-1.ConclusionThese data show high levels of B7-H3 positivity across soft tissue sarcoma subtypes, suggesting its feasibility as a therapeutic target for future sarcoma treatments. Future clinical trials are needed to evaluate whether targeting B7-H3 can provide clinical benefit to help patients with sarcoma.

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.

Platycodin D reduces PD-L1 levels by inhibiting LXR-β activity and combines with nintedanib to enhance the tumor-killing effect of Tcells.

Most tumors are resistant to programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors, which may be due to impaired antigen presentation resulting from the downregulation of major histocompatibility complex class I (MHC-I) expression on tumor cells. We observed that platycodin D (PD), polygalacin D, and platycodin D2, which are plant-derived triterpenoid saponins, significantly reduced PD-L1 levels. RNA sequencing and the PharmMapper database analysis identified liver X receptor β (LXR-β) as a potential PD target. Further studies showed that PD reduces PD-L1 levels by binding to LXR-β and inhibiting LXR-β activity. Coadministration of PD and nintedanib, known to upregulate MHC-I expression, enhanced tumor recognition and killing by Tcells. This study provides new insights into PD applications and mechanisms.

Perioperative chemoimmunotherapy induces strong immune responses and long-term survival in patients with HLA class I-deficient non-small cell lung cancer

BackgroundLoss of human leukocyte antigen (HLA) class I expression and loss of heterozygosity (LOH) are common events implicated in the primary resistance of non-small cell lung cancer (NSCLC) to immunotherapy....