Browse
Submit Data
Databases
API
Help

Dataset Information

10 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Programmed death (PD)-1/PD-ligand 1 blockade mediates antiangiogenic effects by tumor-derived CXCL10/11 as a potential predictive biomarker.

ABSTRACT: Immune checkpoint inhibitor (ICI) programmed death (PD)-1/PD-ligand 1 (PD-L1) blockade has been approved for various cancers. However, the underlying antitumor mechanisms mediated by ICIs and the predictive biomarkers remain unclear. We report the effects of anti-PD-L1/PD-1 Ab in tumor angiogenesis. In syngeneic mouse models, anti-PD-L1 Ab inhibited tumor angiogenesis and induces net-like hypoxia only in ICI-sensitive cell lines. In tumor tissue and serum of ICI-sensitive cell line-bearing mice, interferon-γ (IFN-γ) inducible angiostatic chemokines CXCL10/11 were upregulated by PD-L1 blockade. In vitro, CXCL10/11 gene upregulation by IFN-γ stimulation in tumor cell lines correlated with the sensitivity of PD-L1 blockade. The CXCL10/11 receptor CXCR3-neutralizing Ab or CXCL11 silencing in tumor cells inhibited the antiangiogenic effect of PD-L1 blockade in vivo. In pretreatment serum of lung carcinoma patients receiving anti-PD-1 Ab, the concentration of CXCL10/11 significantly correlated with the clinical outcome. Our results indicate the antiangiogenic function of PD-1/PD-L1 blockade and identify tumor-derived CXCL10/11 as a potential circulating biomarker of therapeutic sensitivity.

SUBMITTER: Mitsuhashi A

PROVIDER: S-EPMC8645761 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

PD-1 checkpoint blockade in advanced melanoma patients: NK cells, monocytic subsets and host PD-L1 expression as predictive biomarker candidates.

Project description:Blockade of the PD-1 receptor has revolutionized the treatment of metastatic melanoma, with significant increases in overall survival (OS) and a dramatic improvement in patient quality of life. Despite the success of this approach, the number of benefitting patients is limited and there is a need for predictive biomarkers as well as a deeper mechanistic analysis of the cellular populations involved in clinical responses. With the aim to find predictive biomarkers for PD-1 checkpoint blockade, an in-depth immune monitoring study was conducted in 36 advanced melanoma patients receiving pembrolizumab or nivolumab treatment at Karolinska University Hospital. Blood samples were collected before treatment and before administration of the second and fourth doses. Peripheral blood mononuclear cells were isolated and stained for flow cytometric analysis within 2 h of sample collection. Overall survival and progression-free survival (PFS) were inversely correlated with CD69 expression NK cells. In the myeloid compartment, high frequencies of non-classical monocytes and low frequencies of monocytic myeloid derived suppressor cells (MoMDSCs) correlated with response rates and OS. A deeper characterization of monocytic subsets showed that PD-L1 expression in MDSCs, non-classical and intermediate monocytes was significantly increased in patients with shorter PFS in addition to correlating inversely with OS. Our results suggest that cellular populations other than T cells can be critical in the outcome of PD-1 blockade treatment. Specifically, the frequencies of activated NK cells and monocytic subsets are inversely correlated with survival and clinical benefit, suggesting that their role as predictive biomarkers should be further evaluated.

| S-EPMC7470181 | biostudies-literature

RAD51Bme Levels as a Potential Predictive Biomarker for PD-1 Blockade Response in Non-Small Cell Lung Cancer.

Project description:Lung cancer (LC) cells frequently express high levels of programmed death-ligand 1 (PD-L1). Although these levels grossly correlate with the likelihood of response to specific checkpoint inhibitors, the response prediction is rather imperfect, and more accurate predictive biomarkers are mandatory. We examined the methylation profile of RAD51B (RAD51Bme) as a candidate predictive biomarker for anti-PD-1 therapy efficacy in non-small cell lung cancer (NSCLC), correlating with patients' outcome. PD-L1 immunoexpression and RAD51Bme levels were analysed in NSCLC samples obtained from patients not treated with anti-PD-1 (Untreated Cohort (#1)) and patients treated with PD-1 blockade (Treated Cohort (#2)). Of a total of 127 patients assessed, 58.3% depicted PD-L1 positivity (PD-L1+). RAD51Bme levels were significantly associated with PD-L1 immunoexpression. Patients with PD-1 blockade clinical benefit disclosed higher RAD51Bme levels (p = 0.0390) and significantly lower risk of disease progression (HR 0.37; 95% CI: 0.15-0.88; p = 0.025). Combining RAD51Bme+ with PD-L1+ improved the sensitivity of the test to predict immunotherapy response. PD-L1+ was also associated with lower risk of death (HR 0.35; 95% CI: 0.15-0.81; p = 0.014). Thus, RAD51Bme levels might be combined with validated predictive biomarker PD-L1 immunostaining to select patients who will most likely experience clinical benefit from PD-1 blockade. The predictive value of RAD51Bme should be confirmed in prospective studies.

| S-EPMC7230458 | biostudies-literature

Programmed death-ligand 1 expression in swine chronic infections and enhancement of interleukin-2 production via programmed death-1/programmed death-ligand 1 blockade.

Project description:IntroductionChronic infections lead to the functional exhaustion of T cells. Exhausted T cells are phenotypically differentiated by the surface expression of the immunoinhibitory receptor, such as programmed death-1 (PD-1). The inhibitory signal is produced by the interaction between PD-1 and its PD-ligand 1 (PD-L1) and impairs the effector functions of T cells. However, the expression dynamics of PD-L1 and the immunological functions of the PD-1/PD-L1 pathway in chronic diseases of pigs are still poorly understood. In this study, we first analyzed the expression of PD-L1 in various chronic infections in pigs, and then evaluated the immune activation by the blocking assay targeting the swine PD-1/PD-L1 pathway.MethodsIn the initial experiments, anti-bovine PD-L1 monoclonal antibodies (mAbs) were tested for cross-reactivity with swine PD-L1. Subsequently, immunohistochemical analysis was conducted using the anti-PD-L1 mAb. Finally, we assessed the immune activation of swine peripheral blood mononuclear cells (PBMCs) by the blockade with anti-PD-L1 mAb.ResultsSeveral anti-PD-L1 mAbs tested recognized swine PD-L1-expressing cells. The binding of swine PD-L1 protein to swine PD-1 was inhibited by some of these cross-reactive mAbs. In addition, immunohistochemical analysis revealed that PD-L1 was expressed at the site of infection in chronic infections of pigs. The PD-L1 blockade increased the production of interleukin-2 from swine PBMCs.ConclusionsThese findings suggest that the PD-1/PD-L1 pathway could be also involved in immunosuppression in chronic infections in pigs. This study provides a new perspective on therapeutic strategies for chronic diseases in pigs by targeting immunosuppressive pathways.

| S-EPMC8589367 | biostudies-literature

Soluble PD-L1 is a predictive and prognostic biomarker in advanced cancer patients who receive immune checkpoint blockade treatment.

Project description:Circulating soluble programmed death-1 ligand (sPD-L1) is measurable in the serum of cancer patients. This study aimed to investigate the significance of sPD-L1 in cancer patients receiving immune checkpoint inhibitor therapy. Blood samples were obtained before and after immune checkpoint inhibitor therapy (January 2015 to January 2019). The study cohort consisted of 128 patients who were diagnosed with non-small cell lung cancer (n = 50), melanoma (n = 31), small cell lung cancer (n = 14), urothelial carcinoma (n = 13), and other cancers (n = 20). Patients with a high level (> 11.0 pg/μL) of sPD-L1 were more likely to exhibit progressive disease compared with those with a low level (41.8% versus 20.7%, p = 0.013). High sPD-L1 was also associated with worse prognosis; the median PFS was 2.9 (95% confidence interval [CI] 2.1-3.7) months versus 6.3 (95% CI 3.0-9.6) months (p = 0.023), and the median OS was 7.4 (95% CI 6.3-8.5) months versus 13.3 (95% CI 9.2-17.4) months (p = 0.005). In the multivariate analyses, high sPD-L1 was an independent prognostic factor for both decreased PFS (HR 1.928, p = 0.038) and OS (HR 1.788, p = 0.004). sPD-L1 levels did not correlate with tissue PD-L1 expression. However, sPD-L1 levels were positively correlated with neutrophil to lymphocyte ratios and negatively correlated with both the proportion and the total number of lymphocytes. We found that high pretreatment sPD-L1 levels were associated with progressive disease and were an independent prognostic factor predicting lower PFS and OS in these patients.

| S-EPMC8492653 | biostudies-literature

Fragment-based screening of programmed death ligand 1 (PD-L1).

Project description:The PD-1 immune checkpoint pathway is a highly validated target for cancer immunotherapy. Despite the potential advantages of small molecule inhibitors over antibodies, the discovery of small molecule checkpoint inhibitors has lagged behind. To discover small molecule inhibitors of the PD-1 pathway, we have utilized a fragment-based approach. Small molecules were identified that bind to PD-L1 and crystal structures of these compounds bound to PD-L1 were obtained.

| S-EPMC6474755 | biostudies-literature

Chemokine C-C motif ligand 21 synergized with programmed death-ligand 1 blockade restrains tumor growth.

Project description:Programmed death-ligand 1 (PD-L1) blockade has revolutionized the prognosis of several cancers, but shows a weak effect on pancreatic cancer (PC) due to poor effective immune infiltration. Chemokine C-C motif ligand 21 (CCL21), a chemokine promoting T cell immunity by recruiting and colocalizing dendritic cells (DCs) and T cells, serves as a potential antitumor agent in many cancers. However, its antitumor response and mechanism combined with PD-L1 blockade in PC remain unclear. In our study, we found CCL21 played an important role in leukocyte chemotaxis, inflammatory response, and positive regulation of PI3K-AKT signaling in PC using Metascape and gene set enrichment analysis. The CCL21 level was verified to be positively correlated with infiltration of CD8+ T cells by the CIBERSORT algorithm, but no significant difference in survival was observed in either The Cancer Genome Atlas or the International Cancer Genome Consortium cohort when stratified by CCL21 expression. Additionally, we found the growth rate of allograft tumors was reduced and T cell infiltration was increased, but tumor PD-L1 abundance elevated simultaneously in the CCL21-overexpressed tumors. Then, CCL21 was further verified to increase tumor PD-L1 level through the AKT-glycogen synthase kinase-3β axis in human PC cells, which partly impaired the antitumor T cell immunity. Finally, the combination of CCL21 and PD-L1 blockade showed superior synergistic tumor suppression in vitro and in vivo. Together, our findings suggested that CCL21 in combination with PD-L1 blockade might be an efficient and promising option for the treatment of PC.

| S-EPMC8586683 | biostudies-literature

mRNA Display Discovery of a Novel Programmed Death Ligand 1 (PD-L1) Binding Peptide (a Peptide Ligand for PD-L1).

Project description:Programmed death ligand 1 (PD-L1) is a critical immune checkpoint ligand whose overexpression on tumor cells provides a mechanism of escape from immune surveillance. The interaction between PD-L1 and PD-1 on T cell lymphocytes suppresses both T cell activation and effector function and is engaged by cancers to dampen antitumor immunity. Here, we used mRNA display to engineer an 18-residue linear peptide that binds to human PD-L1. This peptide, which we term SPAM (signal peptide-based affinity maturated ligand), is nonhomologous to known PD-L1 binding peptides and mAbs, with dissociation constants (KD) of 119 and 67 nM for unglycosylated and glycosylated human PD-L1, respectively. The SPAM peptide is highly selective for human PD-L1 and shows no significant binding to either mouse PD-L1 or human PD-L2. Competition binding assays indicate that the SPAM peptide binding site overlaps with the binding site of PD-1 as well as therapeutic anti-PD-L1 antibodies. Taken together, these results suggest that the SPAM peptide specifically binds to human PD-L1 and could potentially serve as a PD-L1 affinity agent and PD-L1/PD-1 pathway modulator.

| S-EPMC7416570 | biostudies-literature

In vitro Interactions of Chicken Programmed Cell Death 1 (PD-1) and PD-1 Ligand-1 (PD-L1).

Project description:In the present study, we determined the in vitro characteristics and binding interactions of chicken PD-1 (chPD-1) and PD-L1 (chPD-L1) and developed a panel of specific monoclonal antibodies against the two proteins. ChPD-1 and chPD-L1 sequence identities and similarities were lower compared with those of humans and other mammalian species. Furthermore, in phylogenetic analysis, chPD-1 and chPD-L1 were grouped separately from the mammalian PD-1 and PD-L1 sequences. As in other species, chPD-1 and chPD-L1 sequences showed signal peptide, extracellular domain, a transmembrane domain and intracellular domain. Based on the three dimensional (3D) structural homology, chPD-1, and chPD-L1 were similar to 3D structures of mammalian PD-1 and PD-L1. Further, Ig V domain of chPD-1 and the Ig V and Ig C domains of chPD-L1 were highly conserved with the mammalian counterparts. In vitro binding interaction studies using Superparamagnetic Dynabeads® confirmed that recombinant soluble chPD-1/PD-L1 fusion proteins and surface chPD-1/PD-L1 proteins interacted with each other on COS cells. Two monoclonal antibodies specific against chPD-1 and five antibodies against chPD-L1 were developed and their specific binding characteristics confirmed by immunofluorescence staining and Western blotting.

| S-EPMC6930881 | biostudies-literature

Intestinal tolerance is converted to autoimmune enteritis upon PD-1 ligand blockade.

Project description:The B7 family member programmed death-1 ligand (PD-L1) has been shown to play an inhibitory role in the regulation of T cell responses in several organs. However, the role of PD-L1 in regulating tolerance to self-Ags of the small intestine has not been previously addressed. In this study, we investigated the role of PD-L1 in CD8(+) T cell tolerance to an intestinal epithelium-specific Ag using the iFABP-tOVA transgenic mouse model, in which OVA is expressed as a self-Ag throughout the small intestine. Using adoptive transfer of naive OVA-specific CD8(+) T cells, we show that loss of PD-1:PD-L1 signaling, by either Ab-mediated PD-L1 blockade or transfer of PD-1(-/-) T cells, leads to considerable expansion of OVA-specific CD8(+) T cells and their differentiation into effector cells capable of producing proinflammatory cytokines. A fatal CD8(+) T cell-mediated inflammatory response develops rapidly against the small bowel causing destruction of the epithelial barrier, severe blunting of intestinal villi, and recruitment and activation of myeloid cells. This response is highly specific because immune destruction selectively targets the small intestine but not other organs. Collectively, these results indicate that loss of the PD-1:PD-L1 inhibitory pathway breaks CD8(+) T cell tolerance to intestinal self-Ag, thus leading to severe enteric autoimmunity.

| S-EPMC3682217 | biostudies-other

Resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms, predictive factors, and future perspectives.

Project description:PD-1/PD-L1 blockade therapy is a promising cancer treatment strategy, which has revolutionized the treatment landscape of malignancies. Over the last decade, PD-1/PD-L1 blockade therapy has been trialed in a broad range of malignancies and achieved clinical success. Despite the potentially cure-like survival benefit, only a minority of patients are estimated to experience a positive response to PD-1/PD-L1 blockade therapy, and the primary or acquired resistance might eventually lead to cancer progression in patients with clinical responses. Accordingly, the resistance to PD-1/PD-L1 blockade remains a significant challenge hindering its further application. To overcome the limitation in therapy resistance, substantial effort has been made to improve or develop novel anti-PD-1/PD-L1 based immunotherapy strategies with better clinical response and reduced immune-mediated toxicity. In this review, we provide an overview on the resistance to PD-1/PD-L1 blockade and briefly introduce the mechanisms underlying therapy resistance. Moreover, we summarize potential predictive factors for the resistance to PD-1/PD-L1 blockade. Furthermore, we give an insight into the possible solutions to improve efficacy and clinical response. In the following research, combined efforts of basic researchers and clinicians are required to address the limitation of therapy resistance.

| S-EPMC7450549 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data