Programmed Death Ligand-1 Axis Research Articles

NFKB2 mediates colorectal cancer cell immune escape and metastasis in a STAT2/PD‐L1‐dependent manner

This study systematically analyzed the molecular mechanism and function of nuclear factor kappa B subunit 2 (NFKB2) in colorectal cancer (CRC) to investigate the potential of NFKB2 as a therapeutic target for CRC. Various experimental techniques, including RNA sequencing, proteome chip assays, and small molecule analysis, were used to obtain a deeper understanding of the regulation of NFKB2 in CRC. The results revealed that NFKB2 was upregulated in a significant proportion of patients with advanced hepatic metastasis of CRC. NFKB2 played an important role in promoting tumor growth through CD8+ T-cell exhaustion. Moreover, NFKB2 directly interacted with signal transducer and activator of transcription 2 (STAT2), leading to increased phosphorylation of STAT2 and the upregulation of programmed death ligand 1 (PD-L1). Applying a small molecule inhibitor of NFKB2 (Rg5) led to a reduction in PD-L1 expression and improved response to programmed death-1 blockade-based immunotherapy. In conclusion, the facilitated NFKB2-STAT2/PD-L1 axis may suppress immune surveillance in CRC and targeting NFKB2 may enhance the efficacy of immunotherapeutic strategies. Our results provide novel insights into the molecular mechanisms underlying the contribution of NFKB2 in CRC immune escape.

Programmed Cell Death Ligand 1 Immunohistochemical Expression and Cutaneous Melanoma: A Controversial Relationship.

Cutaneous melanoma (CM) is traditionally considered one of the most "immunogenic" tumors, eliciting a high immune response. However, despite the presence of tumor-infiltrating lymphocytes (TILs), melanoma cells use strategies to suppress antitumor immunity and avoid being eliminated by immune surveillance. The PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) axis is a well-known immune escape system adopted by neoplastic cells. Therefore, immunotherapy with PD-1 and PD-L1 inhibitors is quickly becoming the main treatment approach for metastatic melanoma patients. However, the clinical utility of PD-L1 expression assessment in CM is controversial, and the interpretation of PD-L1 scores in clinical practice is still a matter of debate. Nonetheless, the recent literature data show that by adopting specific PD-L1 assessment methods in melanoma samples, a correlation between the expression of such a biomarker and a positive response to PD-1-based immunotherapy can be seen. Our review aims to describe the state-of-the-art knowledge regarding the prognostic and predictive role of PD-L1 expression in CM while also referring to possible biological explanations for the variability in its expressions and related treatment responses.

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs. Malignant GEP-NET cells expressed genes and regulons associated with normal, gastrointestinal endocrine cell differentiation, and fate determination stages. Tumor and lymphoid compartments sparsely expressed immunosuppressive targets commonly investigated in clinical trials, such as the programmed cell death protein-1/programmed death ligand-1 axis. However, infiltrating myeloid cell types within both primary and metastatic GEP-NETs were enriched for genes encoding other immune checkpoints, including VSIR (VISTA), HAVCR2 (TIM3), LGALS9 (Gal-9), and SIGLEC10. Our findings highlight the transcriptomic heterogeneity that distinguishes the cellular landscapes of GEP-NET anatomic subtypes and reveal potential avenues for future precision medicine therapeutics.

Progress of research on PD-1/PD-L1 in leukemia.

Leukemia cells prevent immune system from clearing tumor cells by inducing the immunosuppression of the bone marrow (BM) microenvironment. In recent years, further understanding of the BM microenvironment and immune landscape of leukemia has resulted in the introduction of several immunotherapies, including checkpoint inhibitors, T-cell engager, antibody drug conjugates, and cellular therapies in clinical trials. Among them, the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis is a significant checkpoint for controlling immune responses, the PD-1 receptor on tumor-infiltrating T cells is bound by PD-L1 on leukemia cells. Consequently, the activation of tumor reactive T cells is inhibited and their apoptosis is promoted, preventing the rejection of the tumor by immune system and thus resulting in the occurrence of immune tolerance. The PD-1/PD-L1 axis serves as a significant mechanism by which tumor cells evade immune surveillance, and PD-1/PD-L1 checkpoint inhibitors have been approved for the treatment of lymphomas and varieties of solid tumors. However, the development of drugs targeting PD-1/PD-L1 in leukemia remains in the clinical-trial stage. In this review, we tally up the basic research and clinical trials on PD-1/PD-L1 inhibitors in leukemia, as well as discuss the relevant toxicity and impacts of PD-1/PD-L1 on other immunotherapies such as hematopoietic stem cell transplantation, bi-specific T-cell engager, chimeric antigen receptor T-cell immunotherapy.

Neoadjuvant treatment does not influence PD-L1 expression in stage III non-small-cell lung cancer: a retrospective analysis of tumor samples from the trials SAKK 16/96, 16/00, 16/01, and 16/14

The inclusion of immune checkpoint inhibitors (ICIs) in the treatment of operable stage III non-small-cell lung cancer is becoming a new standard. Programmed death-ligand 1 (PD-L1) protein expression on tumor cells has emerged as the most important biomarker for sensitivity to ICIs targeting the programmed cell death protein 1 (PD-1)-PD-L1 axis. Little is known about the impact of neoadjuvant treatment on PD-L1 expression. We assessed PD-L1 expression by immunohistochemistry (Ventana SP263 assay) on tumor cells in treatment-naive diagnostic tumor samples and matched lung resections from patients with stage III non-small-cell lung cancer included in the Swiss Group for Clinical Cancer Research (SAKK) trials 16/96, 16/00, 16/01, and 16/14. All patients received neoadjuvant chemotherapy (CT) with cisplatin/docetaxel, either as single modality (CT), with sequential radiotherapy [chemoradiation therapy (CRT)] or with the PD-L1 inhibitor durvalumab (CT+ ICI). Overall, 132 paired tumor samples were analyzed from patients with neoadjuvant CT (n= 69), CRT (n= 33) and CT+ ICI (n= 30). For CT and CRT, PD-L1 expression before and after neoadjuvant treatment did not differ significantly (Wilcoxon test, P= 0.94). Likewise, no statistically significant difference was observed between CT and CRT for PD-L1 expression after neoadjuvant treatment (P= 0.97). For CT+ ICI, PD-L1 expression before and after neoadjuvant treatment also did not differ significantly (Wilcoxon test, P > 0.99). Event-free survival and overall survival for patients with downregulation or upregulation of PD-L1 expression after neoadjuvant treatment were similar. In our cohort of patients neoadjuvant treatment did not influence PD-L1 expression, irrespective of the specific neoadjuvant treatment protocol. Dynamic change of PD-L1 expression did not correlate with event-free survival or overall survival.

Traditional Chinese medicine inhibits PD-1/PD-L1 axis to sensitize cancer immunotherapy: a literature review.

The Programmed death-1 (PD-1) and its programmed death-ligand 1 (PD-L1) comprise the PD-1/PD-L1 axis and maintain tumor immune evasion. Cancer immunotherapy based on anti-PD-1/PD-L1 antibodies is the most promising anti-tumor treatment available but is currently facing the thorny problem of unsatisfactory outcomes. Traditional Chinese Medicine (TCM), with its rich heritage of Chinese medicine monomers, herbal formulas, and physical therapies like acupuncture, moxibustion, and catgut implantation, is a multi-component and multi-target system of medicine known for enhancing immunity and preventing the spread of disease. TCM is often used as an adjuvant therapy for cancer in clinical practices, and recent studies have demonstrated the synergistic effects of combining TCM with cancer immunotherapy. In this review, we examined the PD-1/PD-L1 axis and its role in tumor immune escape while exploring how TCM therapies can modulate the PD-1/PD-L1 axis to improve the efficacy of cancer immunotherapy. Our findings suggest that TCM therapy can enhance cancer immunotherapy by reducing the expression of PD-1 and PD-L1, regulating T-cell function, improving the tumor immune microenvironment, and regulating intestinal flora. We hope this review may serve as a valuable resource for future studies on the sensitization of immune checkpoint inhibitors (ICIs) therapy.

Hepatic myofibroblasts exert immunosuppressive effects independent of the immune checkpoint regulator PD-L1 in liver metastasis of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) represents the 4th most common cause of cancer-related deaths in Western countries. Most patients are diagnosed at advanced stages, often already with metastases. The main site of metastasis is the liver and hepatic myofibroblasts (HMF) play a pivotal role in metastatic outgrowth. Immune checkpoint inhibitors (ICI) targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) improved treatment of several cancers but not of PDAC. Therefore, this study aimed to better understand the impact of HMF on PD-L1 expression and immune evasion of PDAC cells during liver metastasis. Formalin-fixed and paraffin embedded biopsy samples or diagnostic resection specimens from liver metastases of 15 PDAC patients were used for immunohistochemical analyses. Serial sections were stained with antibodies directed against Pan-Cytokeratin, αSMA, CD8, and PD-L1. To investigate whether the PD-1/PD-L1 axis and HMF contribute to immune escape of PDAC liver metastases, a stroma enriched 3D spheroid coculture model was established in vitro, using two different PDAC cell lines, HMF, and CD8+ T cells. Here, functional and flow cytometry analyses were conducted. Immunohistochemical analysis of liver tissue sections of PDAC patients revealed that HMF represent an abundant stroma population in liver metastases, with clear differences in the spatial distribution in small (1500 µm) and large (> 1500 μm) metastases. In the latter, PD-L1 expression was mainly located at the invasion front or evenly distributed, while small metastases either lacked PD-L1 expression or showed mostly weak expression in the center. Double stainings revealed that PD-L1 is predominantly expressed by stromal cells, especially HMF. Small liver metastases with no or low PD-L1 expression comprised more CD8+ T cells in the tumor center, while large metastases exhibiting stronger PD-L1 expression comprised less CD8+ T cells being mostly located at the invasion front. HMF-enriched spheroid cocultures with different ratios of PDAC cells and HMF well mimicking conditions of hepatic metastases in situ. Here, HMF impaired the release of effector molecules by CD8+ T cells and the induction of PDAC cell death, an effect that was dependent on the amount of HMF but also of PDAC cells. ICI treatment led to elevated secretion of distinct CD8+ T cell effector molecules but did not increase PDAC cell death under either spheroid condition. Our findings indicate a spatial reorganization of HMF, CD8+ T cells, and PD-L1 expression during progression of PDAC liver metastases. Furthermore, HMF potently impair the effector phenotype of CD8+ T cells but the PD-L1/PD-1 axis apparently plays a minor role in this scenario suggesting that immune evasion of PDAC liver metastases relies on other immunosuppressive mechanisms.

PD-L1: expression regulation.

Programmed death-ligand 1 (PD-L1), expressed on the surface of tumor cells, can bind to programmed cell death-1 (PD-1) on T cells. The interaction of PD-1 and PD-L1 can inhibit T-cell responses by decreasing T-cell activity and accelerating their apoptosis. Various cancers express high levels of PD-L1 and exploit PD-L1/PD-1 signaling to evade T-cell immunity, and immunotherapies targeting the PD-1/PD-L1 axis have been shown to exert remarkable anti-tumor effects; however, not all tumor patients benefit from these therapies. Therefore, study of the mechanisms regulating PD-L1 expression are imperative. In this review, we explore regulation of PD-L1 expression in the contexts of gene transcription, signaling pathways, histone modification and remodeling, microRNAs, long noncoding RNAs, and post-translational modification. Current developments in studies of agents that block PD-L1 and correlations between immunotherapies targeting PD-1/PD-L1 and PD-L1 expression are also summarized. Our review will assist in understanding of PD-L1 expression regulation and discusses the implications of reported findings in cancer diagnosis and immunotherapy.

Suppression of Tumor or Host Intrinsic CMTM6 Drives Antitumor Cytotoxicity in a PD-L1-Independent Manner.

CKLF-like MARVEL transmembrane domain-containing protein 6 (CMTM6) is known to be a regulator of membranal programmed death ligand 1 (PD-L1) stability and a factor associated with malignancy progression, but the effects and mechanisms of CMTM6 on tumor growth, as well as its potential as a target for therapy, are still largely unknown. Here, we show that CMTM6 expression increased with tumor progression in both patients and mice. Ablation of CMTM6 significantly reduced human and murine tumor growth in a manner dependent on T-cell immunity. Tumor CMTM6 suppression broke resistance to immune-checkpoint inhibitors and remodeled the tumor immune microenvironment, as specific antitumor cytotoxicity was enhanced and contributed primarily to tumor inhibition. Without the PD-1/PD-L1 axis, CMTM6 suppression still significantly dampened tumor growth dependent on cytotoxic cells. Furthermore, we identified that CMTM6 was widely expressed on immune cells. T-cell CMTM6 levels increased with sustained immune activation and intratumoral immune exhaustion and affected T cell-intrinsic PD-L1 levels. Host CMTM6 knockout significantly restrained tumor growth in a manner dependent on CD8+ T cells and not entirely dependent on PD-L1. Thus, we developed and evaluated the antitumor efficacy of CMTM6-targeting adeno-associated virus (AAV), which effectively mobilized antitumor immunity and could be combined with various antitumor drugs. Our findings reveal that both tumor and host CMTM6 are involved in antitumor immunity with or without the PD-1/PD-L1 axis and that gene therapy targeting CMTM6 is a promising strategy for cancer immunotherapy.

The role of PD-1/PD-L1 axis in idiopathic pulmonary fibrosis: Friend or foe?

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with a bleak prognosis. Mounting evidence suggests that IPF shares bio-molecular similarities with lung cancer. Given the deep understanding of the programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway in cancer immunity and the successful application of immune checkpoint inhibitors (ICIs) in lung cancer, recent studies have noticed the role of the PD-1/PD-L1 axis in IPF. However, the conclusions are ambiguous, and the latent mechanisms remain unclear. In this review, we will summarize the role of the PD-1/PD-L1 axis in IPF based on current murine models and clinical studies. We found that the PD-1/PD-L1 pathway plays a more predominant profibrotic role than its immunomodulatory role in IPF by interacting with multiple cell types and pathways. Most preclinical studies also indicated that blockade of the PD-1/PD-L1 pathway could attenuate the severity of pulmonary fibrosis in mice models. This review will bring significant insights into understanding the role of the PD-1/PD-L1 pathway in IPF and identifying new therapeutic targets.

Metabolic reprogramming mediated PD-L1 depression and hypoxia reversion to reactivate tumor therapy.

As a promising cancer treatment, photodynamic therapy (PDT) still achieved limited clinical success due to the severe hypoxia and programmed death ligand-1 (PD-L1) over-expressed immunosuppression tumor microenvironment. At present, few methods have been proven to solve these two defects simply and effectively by a single drug or nano-system simultaneously. To ameliorate this situation, we designed and constructed MB@Bu@MnO2 nanoparticles with two-step oxygen regulation ability and PD-1/PD-L1 axis cascade-disruption capacity via a biomineralization method. In such a nanosystem, manganese dioxide albumin (MnO2@Alb) was used as the drug carrier, Butformin (Bu) as mitochondria-associated oxidative phosphorylation (OXPHOS) disruption agent with PD-L1 depression and oxygen reversion ability, and methylene blue (MB) as PDT drug with programmed cell death protein 1 (PD-1) inhibition capacity. Owing to the tumor-responsive capacity of MB@Bu@MnO2 nanoparticles, Bu and MB were selectively delivered and released in tumors. Then, the tumor hypoxia was dramatically reversed by Bu inhibited oxygen consumption, and MnO2 improved oxygen generation. Following this, the reactive oxygen species (ROS) generation was enhanced by MB@Bu@MnO2 nanoparticles mediated PDT owing to the reversed tumor hypoxia. Furthermore, the immunosuppression microenvironment was also obviously reversed by MB@Bu@MnO2 nanoparticles enhanced immunogenic cell death (ICD) and PD-1/PD-L1 axis cascade-disruption, which then enhanced T cell infiltration and improved its tumor cell killing ability. Finally, the growth of solid tumors was significantly depressed by MB@Bu@MnO2 nanoparticles mediated PDT. All in all, this well-designed nanosystem could solve the defects of traditional PDT via PD-1/PD-L1 axis dual disruption and reversing tumor hypoxia by two-step oxygen regulation.

Prognostic stratification based on the levels of tumor-infiltrating myeloid-derived suppressor cells and PD-1/PD-L1 axis in locally advanced rectal cancer.

Although rectal cancer remains somewhat sanctuary to the contemporary immunotherapy, there is increasing knowledge on clinical implications of anti-tumor immunity. This study evaluated the prognostic relevance of two immune-inhibitory functions, myeloid-derived suppressor cells (MDSCs) and programmed cell death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis. Study cohort is comprised of 165 patients with locally advanced rectal cancer who underwent neoadjuvant chemoradiotherapy followed by definitive resection. Using postsurgical tissue microarrays, the number of MDSCs, PD-1+/CD8+ tumor-infiltrating lymphocyte (TIL) ratio, and PD-L1 expression scores in stromal immune cells and tumor cells were assessed. Positive correlation was observed between the PD-1+/CD8+ TIL ratio and number of MDSCs (P < 0.001). The greater the immune infiltrates, the higher the PD-L1 immune cell score (P < 0.001). MDSCHigh, PD-1+/CD8+ TILHigh, PD-L1 immune cell scoreLow, and PD-L1 tumor H-scoreHigh were associated with worse disease-free survival (DFS) (P < 0.001, P = 0.042, 0.047, and P < 0.001, respectively). To integrate the adverse effects of MDSCHigh, PD-1+/CD8+ TILHigh, and either PD-L1 immune cell scoreLow (set I) or tumor H-scoreHigh (set II), prognostic risks were stratified according to the number of factors: 0, 1, and 2-3 (P < 0.001 for I and II). On multivariate analyses, patients with multiple risk factors for set I and II had worse prognosis (P < 0.001; 2-3 vs. 0 for models I and II), and the two prognostic models had acceptable predictability. In this study, integration of the prognostic impact of MDSCs and PD-1/PD-L1 stratified the long-term risks of patients with locally advanced rectal cancer. Thus, further exploration could be focused to the identified subset of patients carrying worse prognosis, where potential benefits could be derived by targeting the two components contributing to the immunosuppressive microenvironment.

Epigenetic modifications: Critical participants of the PD‑L1 regulatory mechanism in solid tumors (Review).

Immune checkpoint inhibitors targeting the programmed cell death protein 1 (PD-1)/programmed death ligand 1 (PD-L1) axis have achieved marked and durable efficacy in patients with different solid tumors and have improved their survival. However, the presence of primary or acquired resistance to immune checkpoint blockades results in only a small fraction of patients benefiting from the treatment. An increasing number of preclinical studies have reported that PD-L1 expression in tumor cells is involved in a number of epigenetic changes, including histone modifications, non-coding RNA regulation and DNA methylation. In addition, multiple epigenetic targeting drugs have been demonstrated to directly or indirectly interfere with PD-L1 expression in various cancer models. This provides opportunities to better characterize the regulatory mechanisms of PD-L1 expression and explore novel therapeutic strategies to improve immunosuppressant response rates and overcome drug resistance. The present review focuses on the latest findings and evidence on the epigenetic mechanism regulating PD-L1 expression and discusses the biological and clinical implications of this regulatory mechanism in solid tumors. A rational combination of epigenetic regulation and PD-1/PD-L1 axis blockade may improve the prognosis of patients with solid tumors.

Upregulation of PD-1 Expression and High sPD-L1 Levels Associated with COVID-19 Severity

COVID-19 has several mechanisms that can lead to lymphocyte depletion/exhaustion. The checkpoint inhibitor molecule programmed death protein 1 (PD-1) and its programmed death-ligand 1 (PDL-1) play an important role in inhibiting cellular activity as well as the depletion of these cells. In this study, we evaluated PD-1 expression in TCD4+, TCD8+, and CD19+ lymphocytes from SARS-CoV-2-infected patients. A decreased frequency of total lymphocytes and an increased PD-1 expression in TCD4+ and CD19+ lymphocytes were verified in severe/critical COVID-19 patients. In addition, we found a decreased frequency of total monocytes with an increased PD-1 expression on CD14+ monocytes in severe/critical patients in association with the time of infection. Moreover, we observed an increase in sPD-L1 circulant levels associated with the severity of the disease. Overall, these data indicate an important role of the PD-1/PDL-1 axis in COVID-19 and may provide a severity-associated biomarker and therapeutic target during SARS-CoV-2 infection.

In vivo positron emission tomography imaging for PD-L1 expression in cancer using aptamer

The programmed death-1 (PD-1) receptor is an immunosuppressive receptor expressed on activated T-cells that elicits an inhibitory signal upon the engagement of its ligand, which is the programmed death ligand 1 (PD-L1). Recent studies have shown that PD-1/PD-L1 blockade can enhance endogenous antitumor immunity. Thus, the PD-1/PD-L1 axis may be a potential therapeutic target for cancer immunotherapy. Aptamers are oligonucleotides with high specificity and affinity for target molecules and promising candidates for molecular imaging and targeted therapy. 68Ga is an attractive radionuclide that serves as a low-cost alternative to cyclotron-produced positron emission tomography (PET) radionuclides. In this study, we developed a 68Ga-labeled PD-L1 aptamer and investigated its target specificity and utility for in vivo PET scanning. In the first part of our study, we evaluated the binding affinity of three PD-L1 aptamers in PD-L1-positive (H1975 and B16F10) and negative (A549 and HT-29) tumor cells by flow cytometry and confocal microscopy. Optical imaging studies of PD-L1 aptamers were performed in H1975 tumor-bearing mice, and the aptamer with the highest binding affinity to PD-L1 positive tumors was selected. PD-L1 aptamers were radiolabeled with 68Ga. PET was performed for in vivo imaging of the 68Ga-NOTA-PD-L1 aptamer in H1975 tumor-bearing mice (PD-L1-positive cells) and A549 tumor-bearing mice (PD-L1-negative cells). Flow cytometry and confocal microscopy showed that PD-L1 aptamers had strong binding to PD-L1-positive H1975 and B16F10 cells. In contrast, PD-L1-negative A549 and HT-29 cells showed low binding to PD-L1 aptamers. Optical imaging studies of H1975 tumor-bearing mice showed the highest uptake of the 2198-06-07 PD-L1 aptamer. PET of 68Ga-NOTA-PD-L1 aptamers demonstrated increased uptake into PD-L1-positive H1975 tumors compared with PD-L1-negative A549 tumors. We confirmed that 68Ga-NOTA-PD-L1 aptamers facilitated the visualization of PD-L1 expression by in vivo PET scanning. These data suggest that 68Ga-NOTA-PD-L1 aptamers could potentially act as tracers for imaging for PD-L1-positive cancers.

Soluble PD-L1 Expression After Intravenous Treatment of Cancer Patients With Selenite in Phase I Clinical Trial.

A high expression level of programmed death-ligand 1 (PD-L1) is observed in different types of cancers (particularly lung cancer). Soluble (s)PD-L1 may be used as a prognostic marker and a target for anti-cancer immunity, as well as, predicting gene therapy or systemic immunotherapy in blocking the PD-1 and PD-L1 checkpoint. Studies that evaluate the effects of the immune regulator selenium on PD-L1 expression show ambiguous results. Thus, we aimed to analyze sPD-L1 levels in samples from patients who underwent different dosages of selenite treatment in phase I clinical trial. We hypothesized that selenite modulates the sPD-L1 levels in the plasma as a consequence of the suggested mode of action of selenotherapy in cancer patients. In conclusion, our results support the view that selenotherapy does not substantially affect the PD-1/PD-L1 axis judged by sPD-L1 analysis. Furthermore, no significant correlation was observed between the survival and sPD-L1 expression nor sPD-L1 changes. However, due to a dynamic individual sPD-L1 profile and a high variation in survival, we suggest that further studies are needed to identify whether individual patients can be benefited from combinational seleno- and anti-PD-L1 therapy.

Burgeoning Exploration of the Role of Natural Killer Cells in Anti-PD-1/PD-L1 Therapy

Antibodies targeting programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) have been considered breakthrough therapies for a variety of solid and hematological malignancies. Although cytotoxic T cells play an important antitumor role during checkpoint blockade, they still show a potential killing effect on tumor types showing loss of/low major histocompatibility complex (MHC) expression and/or low neoantigen load; this knowledge has shifted the focus of researchers toward mechanisms of action other than T cell-driven immune responses. Evidence suggests that the blockade of the PD-1/PD-L1 axis may also improve natural killer (NK)-cell function and activity through direct or indirect mechanisms, which enhances antitumor cytotoxic effects; although important, this topic has been neglected in previous studies. Recently, some studies have reported evidence of PD-1 and PD-L1 expression in human NK cells, performed exploration of the intrinsic mechanism by which PD-1/PD-L1 blockade enhances NK-cell responses, and made some progress. This article summarizes the recent advances regarding the expression of PD-1 and PD-L1 molecules on the surface of NK cells as well as the interaction between anti-PD-1/PD-L1 drugs and NK cells and associated molecular mechanisms in the tumor microenvironment.

The genetic influence of PD-1/PD-L1 axis single nucleotide polymorphisms on the incidence of type 1 diabetes mellitus in pediatric Egyptian patients

BackgroundThe increasing prevalence of diabetes mellitus (DM) is one of the most challenging public health issues. The destruction of insulin-producing cells in the islets of Langerhans is the hallmark of type 1 diabetes mellitus (T1DM) as an autoimmune disease. In the current case–control study, the role of single nucleotide polymorphisms (SNPs) was investigated within the programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitory axis and their association with T1DM susceptibility in a sample of Egyptian pediatric patients. The study included 80 T1DM pediatric patients and 76 healthy control subjects. The patients were recruited from Beni-Suef University Hospital’s Pediatric Endocrinology Outpatient Clinic. Genotyping of PD-1 SNP (rs 34819629) and PD-L1 SNPs (rs 2297137 and rs 4143815) was performed by TaqMan allelic discrimination technique via real-time polymerase chain reaction (RT-PCR). The patients were subjected to a thorough clinical examination and history taking.ResultGenotyping of PD-1 (rs 34819629) revealed that all of the enrolled patients and the control group inherited the same genotype (GG genotype). With regard to PDL-1 rs4143815 SNP and the risk of T1DM occurrence, our comparison did not reveal the presence of an association between the different genetic models (general, dominant, and recessive) of the SNP and the risk of T1DM (p = 0.078 and p = 0.055; for the general genetic model, p = 0.061 and p = 0.169 for the dominant and the recessive types, respectively). Regarding PDL-1 rs2297137 SNP, the results of this study demonstrated that the risk of T1DM was significantly associated with the recessive genetic model (p = 0.007) as the diabetic group’s predominant G allele was higher compared to the control group.ConclusionThe findings obtained supported the hypothesis that the predominant G allele of PD-L1 rs2297137 is associated with the development of T1DM. Chronic hyperglycemia and long-standing diabetes problems are linked to both PD-L1 SNPs (rs4143815 and rs2297137). Future studies with a more significant number of patients are required to support our results.

Circ_0092012 knockdown restrains non-small cell lung cancer progression by inhibiting cell malignant phenotype and immune escape through microRNA-635/programmed death ligand 1 axis

ABSTRACT Circular RNAs have been reported to play roles in non-small cell lung cancer (NSCLC) progression. Herein, this work aimed to investigate the potential value of circ_0092012 in NSCLC progression. Levels of genes and proteins were detected using quantitative reverse transcription-polymerase chain reaction and Western blot, respectively. The growth, malignant phenotypes and immune escape in NSCLC were investigated. The binding between microRNA (miR)-635 and circ_0092012 or programmed death ligand 1 (PDL1) was verified. Circ_0092012 was highly expressed in NSCLC. Circ_0092012 deficiency suppressed NSCLC cell proliferation, invasion and migration, moreover, as well as was able to inhibit the apoptosis of CD8 + T cells and induce higher interferon-γ and tumor necrosis factor-α levels when co-cultured with peripheral blood mononuclear cells. Mechanistically, circ_0092012 sponged miR-635, which targeted PDL1. Further rescue experiments suggested that the anticancer effects of circ_0092012 knockdown were reversed by miR-635 inhibition. Additionally, miR-635 re-expression suppressed NSCLC cell malignant phenotypes mentioned above and immune escape, which were attenuated by PDL1 overexpression. Moreover, circ_0092012 deletion retarded NSCLC growth in vivo. In all, circ_0092012 knockdown suppressed NSCLC cell oncogenic phenotypes and immune escape by miR-635/PDL1 axis.

LncRNA EGFR-AS1 facilitates leiomyosarcoma progression and immune escape via the EGFR-MYC-PD-L1 axis.

this study aimed to investigate the role of long non-coding RNA (lncRNA) epidermal growth factor receptor antisense RNA 1 (EGFR-AS1), an antisense transcript of EGFR, in leiomyosarcoma (LMS) and the underlying mechanisms. levels of EGFR-AS1 and programmed death ligand 1 (PD-L1) were measured in LMS tissues and cell lines using quantitative real-time PCR (qRT-PCR), as well as western blotting and/or immunohistochemical staining; flow cytometry was employed to validate the role of EGFR-AS1 in altering the activity of CD8+ T cells; interaction of EGFR-AS1 and EGFR was determined by fluorescent in situ hybridization (FISH) and RNA pull-down; regulation of MYC on the PD-L1 promoter was assessed by chromatin immunoprecipitation (ChIP); a xenograft in vivo tumor growth assay was applied to verify the EGFR-AS1/EGFR/MYC/PD-L1 axis in vivo. up-regulation of EGFR-AS1 and PD-L1 in LMS tissues was negatively correlated with CD8+ T-cell infiltration; EGFR-AS1 positively regulated PD-L1, thereby strengthening interaction of LMS cells and CD8+ T cells and triggering CD8+ T cell apoptosis via the PD-1/PD-L1 checkpoint; EGFR-AS1 co-localized and interacted with EGFR to promote MYC activity; MYC was identified as a transcriptional activator of PD-L1. lncRNA EGFR-AS1 was demonstrated to increase PD-L1 expression through the EGFR/MYC pathway in LMS cells, thereby repressing T-cell infiltration and contributing to immune escape.