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Results for “Programmed Cell Death 1 Receptor”

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PubMed2020

Combination of cyclin-dependent kinase and immune checkpoint inhibitors for the treatment of bladder cancer.

BACKGROUND: Perturbation of the CDK4/6 pathway is frequently observed in advanced bladder cancer. We investigated the potential of targeting this pathway alone or in combination with chemotherapy or immunotherapy as a therapeutic approach for the treatment of bladder cancer METHODS: The genetic alterations of the CDK4/6 pathway in bladder cancer were first analyzed with The Cancer Genome Atlas database and validated in our bladder cancer patient-derived tumor xenografts (PDXs). Bladder cancer cell lines and mice carrying PDXs with the CDK4/6 pathway perturbations were treated with a CDK4/6 inhibitor palbociclib to determine its anticancer activity and the underlying mechanisms. The combination index method was performed to assess palbociclib and gemcitabine drug-drug interactions. Syngeneic mouse bladder cancer model BBN963 was used to assess whether palbociclib could potentiate anti-PD1 immunotherapy. RESULTS: Of the 413 bladder cancer specimens, 79.2% harbored pertubations along the CDK4/6 pathway. Palbociclib induced G0/G1 cell cycle arrest but with minimal apoptosis in vitro. In mice carrying PDXs, palbociclib treatment reduced tumor growth and prolonged survival from 14 to 32 days compared to vehicle only controls (p = 0.0001). Palbociclib treatment was associated with a decrease in Rb phosphorylation in both cell lines and PDXs. Palbociclib and gemcitabine exhibited antagonistic cytotoxicity in vitro (CI > 3) and in vivo, but palbociclib significantly enhanced the treatment efficacy of anti-PD1 immunotherapy and induced CD8+ T lymphocyte infiltration in syngeneic mouse models. CONCLUSIONS: The CDK4/6 pathway is feasible as a potential target for the treatment of bladder cancer, especially in combination with immunotherapy. A CDK4/6 inhibitor should not be combined with gemcitabine.

Animals↗

PubMed2025

High baseline PD-1+ CD8 T Cells and TIGIT+ CD8 T Cells in circulation associated with response to PD-1 blockade in patients with non-small cell lung cancer.

Blockade of PD-1 or its ligand PD-L1 with antibodies revolutionized treatment for stage III and IV non-small cell lung cancer (NSCLC) since FDA approval in 2015. However, resistance to PD-1/PD-L1 blockade remains a challenge, highlighting the need for biomarkers. This study analyzed 36 stage III and IV NSCLC patients, classified as responders or non-responders by iRECIST criteria. Peripheral blood mononuclear cells collected at baseline and post-treatment were examined for surface and intracellular markers via flow cytometry. CITE sequencing of CD8 T cells from three patients and plasma ctDNA analysis from 13 patients was performed using an ultrasensitive barcoding and next-generation sequencing method. Phenotypic analysis of CD8 T cells revealed higher TIGIT and PD-1 expression at baseline in responders compared to non-responders. Long-term responders (> 21 months) exhibited increased TCF-1+PD-1+ CD8 T cell frequencies relative to shorter-term responders (> 15 months) and non-responders. CITE sequencing revealed intrinsic differences in immune regulation pathways between responders and non-responders. Finally, non-responders showed elevated and increasing ctDNA levels post-treatment, correlating with declining TCF-1+PD-1+ CD8 T cells. Our data suggests combining CD8 T cell analysis with ctDNA dynamics could identify promising biomarkers for monitoring clinical response and treatment efficacy to PD-1/PD-L1 blockade in NSCLC.

Humans↗

PubMed2006

The genetics of systemic lupus erythematosus: understanding how SNPs confer disease susceptibility.

The identification of genes for autoimmune diseases is just the first step towards our understanding of disease pathogenesis. In investigating how mutations, deletions or other types of polymorphic defects occur, it is important to determine the pathways and the mechanisms through which susceptibility leads to disease. In this review I touch on three examples of studies that have attempted to understand the mechanisms of genetic susceptibility in three genes identified recently for systemic lupus erythematosus: PDCD1, PTPN22 and IRF5. We are just beginning to comprehend and much needs to be done.

Animals↗

PubMed2004

Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies.

Recently, a polymorphism in intron 4 (G/A) of the programmed cell death 1 ( PDCD1) gene was shown to be associated with systemic lupus erythematosus (SLE) risk in familial and sporadic patients of European, European American, and Mexican origin. In this investigation, we examined the role of this polymorphism in 311 SLE patients (276 European Americans and 35 African Americans) and 390 age-matched healthy controls (359 European Americans and 31 African Americans). The frequency of the A allele was significantly higher in European American controls than in African American controls (0.107 vs. 0.048; P=0.046). There was no significant difference in the frequency of the A allele between SLE cases and controls in either the European American (0.107 vs. 0.129; P=0.84) or African American (0.048 vs. 0.100; P=0.25) cohort. However, after adjustment for the status of the antiphospholipid antibodies (APA) in the logistic regression analysis, the risk for SLE associated with the PDCD1 polymorphism was statistically significant. The APA-adjusted odds ratio (OR) between A allele carriers (AA + AG genotypes) versus the GG genotype showed a modest association with SLE risk in European Americans (OR=1.52, 95% CI: 1.02-2.27; P=0.039), African Americans (OR=2.89, 95% CI: 0.61-13.76; P=0.183), and the ethnicity-combined sample (OR=1.59, 95% CI: 1.08-2.34; P=0.019). Furthermore, we observed that the A allele carriers were protected against the occurrence of APA in both controls (OR=0.399, 95% CI: 0.19-0.82; P=0.0098) and SLE cases (OR=0.566, 95% CI: 0.32-1.01; P=0.054). Our data indicate polymorphism in intron 4 of the PDCD1 gene affects the occurrence of APA and may slightly modify the risk of sporadic SLE.

Adolescent↗

PubMed2005

Ethnic differences in allele frequency of autoimmune-disease-associated SNPs.

Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE. Because these reports on association were not always evaluated in multiple ethnic groups and because ethnic difference in allele frequency of the variants has been also reported, we investigated allele frequencies of nine SNPs in four autoimmune-disease-associated loci in Caucasian, African-descent, and Japanese populations. Although SNPs in PADI4 had similar allele frequency among three groups [maximal difference 11%; (P >0.05)], the other three loci revealed statistically significant allele frequency differences (maximal difference 39% (P <0.00001), 13% (P <0.00001), and 8% (P <0.00001) in SLC22A4, PDCD1, and PTPN22, respectively). Of note, three SNPs in the three loci that had allele frequency more than 8% in the Caucasian population were either not polymorphic at all or extremely rare in the Japanese population. Our data suggest that ethnic variations of polymorphisms should be evaluated in detail, and differences should be incorporated into investigations of susceptibility variants for common diseases.

Antigens, CD↗

PubMed2006

Programmed death-1 gene polymorphisms in patients with systemic lupus erythematosus in Taiwan.

To investigate the role of programmed cell death-1 (PD-1) gene polymorphisms in the development of systemic lupus erythematosus (SLE) in Taiwan, 109 patients with SLE and 100 healthy controls were enrolled in this study. The PD-1 gene polymorphisms were determined by the method of polymerase chain reaction/restriction fragment length polymorphism. This study showed that the genotype distributions of PD-1 7209 C/T polymorphisms were significantly different between the patients with SLE and controls (P=0.002, Pc=0.018). The frequencies of the PD-1 7209 C/C genotype and PD-1 7209 C allele were significantly higher in the patients with SLE than those of the controls (P=0.001, OR=2.6, 95% CI=1.5-4.6, and P=0.002, OR=2.1, 95% CI=1.3-3.4, Pc=0.018, respectively). Moreover, the association of PD-1 7209 C with susceptibility to SLE was independent of the PD-1 ligand. This study also showed that the PD-1-536 A 7146 G 7209 C 7499 G haplotype was associated with the development of SLE in Taiwan.

Adult↗

PubMed2006

HBcAg-specific CD4+CD25+ regulatory T cells modulate immune tolerance and acute exacerbation on the natural history of chronic hepatitis B virus infection.

Acute exacerbations (AEs) of chronic hepatitis B (CH-B) are accompanied by increased T cell responses to hepatitis B core and e antigens (HBcAg/HBeAg). Why patients are immunotolerant (IT) to the virus and why AEs occur spontaneously on the immunoactive phase remain unclear. The role of HBcAg-specific CD4(+)CD25(+) regulatory T (T(reg)) cells in AE and IT phases was investigated in this study. The SYFPEITHI scoring system was employed to predict MHC class II-restricted epitope peptides on HBcAg overlapping with HBeAg that were used for T(reg)-cell cloning and for the construction of MHC class II tetramers to measure T(reg) cell frequencies (T(reg) f). The results showed that HBcAg-specific T(reg) f declined during AE accompanied by increased HBcAg peptide-specific cytotoxic T lymphocyte frequencies. Predominant Foxp3-expressing T(reg) cell clones were generated from patients on the immune tolerance phase, while the majority of Th1 clones were obtained from patients on the immunoactive phase. T(reg) cells from liver and peripheral blood of CH-B patients express CD152 and PD1 antigens that exhibit suppression on PBMCs proliferation to HBcAg. These data suggest that HBcAg peptide-specific T(reg) cells modulate the IT phase, and that their decline may account for the spontaneous AEs on the natural history of chronic hepatitis B virus infection.

Adolescent↗

PubMed2026

Intratumoral PD-1+LAG-3+CD8+ T cells are associated with improved prognosis in gastric cancer.

PURPOSE: PD-1 and LAG-3 are frequently used as markers of T cell exhaustion, yet the prognostic relevance and phenotypic characteristics of PD-1+LAG-3+CD8+ T cells in gastric cancer (GC) remain poorly defined. This study aimed to investigate their association with clinical outcomes and characterize their immune characteristics across independent GC cohorts. METHODS: Four independent GC cohorts were analyzed: the Zhongshan Hospital cohort (ZSGC, n = 298), The Cancer Genome Atlas cohort (TCGA, n = 371), an Immune Checkpoint Blockade cohort (ICB, n = 45), and the Yonsei cohort (n = 433). Intratumoral PD-1+LAG-3+CD8+ T cell infiltration was quantified by immunofluorescence staining and transcriptomic gene signature scoring. Survival analysis was performed using Kaplan-Meier estimation and multivariate Cox regression. Functional characterization was performed by flow cytometry on resected GC tissue. The immune microenvironment composition was evaluated using computational analyses. RESULTS: PD-1+LAG-3+CD8+ T cells were enriched within tumors compared to adjacent normal mucosa, and their infiltration correlated with advanced tumor stage, poor differentiation, microsatellite instability, and Epstein-Barr virus (EBV)-positive molecular subtypes. High intratumoral infiltration was significantly associated with improved overall survival in both the ZSGC and TCGA cohorts, whereas single-positive PD-1+CD8+ or LAG-3+CD8+ T cells showed no such association. In the ICB cohort, higher infiltration was associated with a higher response rate to pembrolizumab. Intratumoral PD-1+LAG-3+CD8+ T cells exhibit an activated phenotype characterized by increased expression of CD137, IFN-γ, perforin, and CXCL13, along with elevated TCF7 and lower PD-1 levels, suggesting a tumor-reactive, pre-exhausted state. High infiltration was further associated with an immune-active tumor microenvironment. CONCLUSIONS: High intratumoral infiltration of PD-1+LAG-3+CD8+ T cells is associated with favorable prognosis and an immune-active microenvironment in GC. These cells display phenotypic features consistent with a pre-exhausted state and may serve as independent prognostic biomarkers and candidate predictive biomarkers for immunotherapy stratification.

Humans↗

PubMed2026

Pharmacologic inhibition of SOX9-CDK4 by CYD-4-61 impairs gastric adenocarcinoma growth and amplifies anti-PD-1 response.

Gastric adenocarcinoma (GAC) remains a leading cause of cancer-related mortality, particularly in patients with peritoneal carcinomatosis, for whom effective therapies are limited. We investigated the therapeutic efficacy and molecular mechanism of CYD-4-61, a BAX activator, using human GAC cell lines, patient-derived xenograft models, genetically engineered mouse models, and a syngeneic mouse model. CYD-4-61 potently inhibited tumor cell proliferation, induced apoptosis, and suppressed cancer stem cell-like properties, with enhanced activity in radiation-resistant GAC cells. Mechanistically, CYD-4-61 activated the BAX-caspase pathway, leading to SOX9 protein reduction. Integrated bulk and single-cell transcriptomic analyses identified SOX9-dependent transcriptional programs as major targets of CYD-4-61. Functional rescue experiments together with chromatin immunoprecipitation and CUT&RUN analyses supported CDK4 as a SOX9-regulated gene and demonstrated suppression of the SOX9-CDK4 regulatory axis following CYD-4-61 treatment. In multiple preclinical models, CYD-4-61 significantly inhibited tumor growth and improved the therapeutic response to anti-programmed cell death protein 1 (PD-1) therapy while modulating the tumor immune microenvironment. Clinically, co-expression of SOX9 and CDK4 was associated with diffuse-type GAC and poor patient outcomes. These findings identify the BAX-SOX9-CDK4 axis as an important mechanism contributing to the antitumor activity of CYD-4-61 and provide a strong preclinical rationale for its further development as a therapeutic strategy for aggressive GAC.

Animals↗

PubMed2006

Rejuvenating exhausted T cells during chronic viral infection.

In a recent paper in Nature, show that the immunoreceptor PD-1 is upregulated by "exhausted" T cells during the chronic phase of viral infection in mice. Remarkably, blocking the interaction between PD-1 and its ligand, PD-L1, reactivates these T cells and reduces viral load.

Animals↗

PubMed2004

PD-1 ligands, negative regulators for activation of naive, memory, and recently activated human CD4+ T cells.

We examined the role of the PD-1 pathway on the activation of naive, memory, and recently activated human CD4+ T cells to test whether they responded differently. PD-1 ligand blockade modestly enhanced the percentage of responding T cells and production of IFN-gamma in a primary response to myelin basic protein (MBP) in normal donors. PD-1 ligand blockade strongly enhanced proliferation and cytokine production by memory or recently activated T cells (tetanus toxoid and MBP). Blockade of PD-L1 alone had more effect than PD-L2, consistent with its higher expression on ex vivo dendritic cells; furthermore, anti-PD-L1 plus anti-PD-L2 resulted in the greatest enhancement. Moreover, PD-L1-Ig inhibited anti-CD3 induced activation of naive, memory, and recently activated CD4+ T cells. Together, our data demonstrated PD-1 functioned as a negative regulatory pathway on naive T cells during a primary response, and more potently, on memory or recently activated T cells during a secondary response.

Antigens, CD↗

PubMed2024

Fecal microbiota transplantation improves anti-PD-1 inhibitor efficacy in unresectable or metastatic solid cancers refractory to anti-PD-1 inhibitor.

The gut microbiome significantly influences immune responses and the efficacy of immune checkpoint inhibitors. We conducted a clinical trial (NCT04264975) combining an anti-programmed death-1 (PD-1) inhibitor with fecal microbiota transplantation (FMT) from anti-PD-1 responder in 13 patients with anti-PD-1-refractory advanced solid cancers. FMT induced sustained microbiota changes and clinical benefits in 6 of 13 patients, with 1 partial response and 5 stable diseases, achieving an objective response rate of 7.7% and a disease control rate of 46.2%. The clinical response correlates with increased cytotoxic T cells and immune cytokines in blood and tumors. We isolated Prevotella merdae Immunoactis from a responder to FMT, which stimulates T cell activity and suppresses tumor growth in mice by enhancing cytotoxic T cell infiltration. Additionally, we found Lactobacillus salivarius and Bacteroides plebeius may inhibit anti-tumor immunity. Our findings suggest that FMT with beneficial microbiota can overcome resistance to anti-PD-1 inhibitors in advanced solid cancers, especially gastrointestinal cancers.

Adult↗

PubMed2005

PD-L1 is expressed by human renal tubular epithelial cells and suppresses T cell cytokine synthesis.

T cell activation is affected by both stimulatory and inhibitory co-signaling. MHC class II-expressing renal tubular epithelial cells (TEC) can function as APC for T cells. To study the influence of inhibitory ligands on TEC-mediated T cell activation, we examined the expression of programmed death ligand-1 (PD-L1) on human TEC line HK-2 cells, as well as in normal and diseased kidney samples. RT-PCR, FACS, and immunocytochemistry showed that PD-L1 is constitutively expressed on HK-2 cells, and is dramatically upregulated by IFN-gamma. In situ hybridization and immunohistochemical staining revealed constitutive low expression of PD-L1 on proximal tubules at both mRNA and protein levels in normal kidneys, but much higher expression in kidneys with type IV lupus nephritis. In vitro, pretreatment of IFN-gamma-stimulated HK-2 cells with anti-PD-L1 significantly enhanced IL-2 secretion from cocultured, mitogen-activated Jurkat or human peripheral blood T cells. These results suggest that the PD-L1:PD-1 pathway negatively regulates T cell activation by TEC, and may play an inhibitory role in TEC-mediated immune activation and immunopathology in the kidney.

Antigens, CD↗

PubMed2004

Genetics of human systemic lupus erythematosus: the emerging picture.

Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease with partially understood etiology, which can affect virtually any organ. Despite suggestions to the contrary, SLE is proving to be a reliable phenotype for genetic studies. Similar to many other autoimmune diseases, SLE demonstrates a complex pattern of inheritance that is consistent with the involvement of multiple susceptibility genes as well as environmental risk factors. During the past several years, some new candidate genes have been implicated in induction of SLE through association studies, and multiple susceptibility regions have been detected through genome-wide linkage studies. Many of the susceptibility effects have been confirmed by independent studies.

Antigens, CD↗

PubMed2004

The expression of B7-H1 on keratinocytes in chronic inflammatory mucocutaneous disease and its regulatory role.

PD-1 and its ligands, B7-H1/PD-L1 and B7-DC/PD-L2, have been identified recently as CD28-B7 family molecules that are implicated in immune regulation. Lichen planus (LP) is a T cell-mediated chronic inflammatory mucocutaneous disease. We investigated the expression and function of PD-1 and its two ligands in LP. Immunohistochemical examination revealed the abundant expression of PD-1 and B7-H1 in infiltrating T cells and macrophages, and lower-level expression of B7-DC on macrophages in the subepithelium. Interestingly, substantial expression of B7-H1 on keratinocytes (KCs) was found close to the numerous T cell infiltrates in the subepithelium. Unstimulated cultured KCs expressed both B7-H1 and B7-DC, and their expression was upregulated by proinflammatory cytokines, particularly IFN-gamma. The T-cell proliferative responses and IFN-gamma production that were induced by IFN-gamma-treated KCs were augmented preferentially by anti-B7-H1 mAb, but not by anti-B7-DC mAb. These results indicate the regulatory role of B7-H1 on KCs in the interactions with T cells. Our results suggest that the induction of B7-H1 on KCs may play an important role in tolerance induction in the inflamed oral mucosa and skin.

Adult↗

PubMed2003

The genetics of human systemic lupus erythematosus.

Genetic dissection of human systemic lupus erythematosus (SLE) has been under intense studies during the past decade. Although the complexity inherent to polygenic, multifactorial diseases is challenging, several new insights have been obtained in the past several years using linkage and association studies of families containing SLE patients as well as case-control studies of populations. In addition, recent advances in our understanding of the human genome and emerging technology have been providing new tools in analyses of complex traits, such as SLE. An overview of our current understanding of the genetic basis of SLE and a brief review of findings of linkage and association studies are described here.

Animals↗

PubMed2006

The road to recovery: translating PD-1 biology into clinical benefit.

Negative immune regulation can result in the poor control of virus replication in chronic infections but is probably important to prevent tissue damage from chronic immune activation. Three recent studies have shown that programmed cell death (PD)-1 expression on T cells correlates with viral load in HIV infection, and that interrupting PD-1 signaling using an antagonistic antibody rejuvenates T-cell effector functions in vitro. These findings have important implications for potential therapies for chronic infection and, perhaps, for improved tumor immunity. Here, we discuss impending issues in the translation to clinical studies in light of recent adverse events with costimulatory antibody therapy.

Animals↗

PubMed2006

PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis.

Interactions between PD-1 and its two differentially expressed ligands, PD-L1 and PD-L2, attenuate T cell activation and effector function. To determine the role of these molecules in autoimmune disease of the CNS, PD-1-/-, PD-L1-/- and PD-L2-/- mice were generated and immunized to induce experimental autoimmune encephalomyelitis (EAE). PD-1-/- and PD-L1-/- mice developed more severe EAE than wild type and PD-L2-/- mice. Consistent with this, PD-1-/- and PD-L1-/- cells produced elevated levels of the pro-inflammatory cytokines IFN-gamma, TNF, IL-6 and IL-17. These results demonstrate that interactions between PD-1/PD-L1, but not PD-1/PDL-2, are crucial in attenuating T cell responses in EAE.

Animals↗