Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PDL1 Expression on Plasma and Dendritic Cells in Myeloma Bone Marrow Suggests Benefit of Targeted anti PD1-PDL1 Therapy.

ABSTRACT: In this study we set out to investigate whether anti PDL1 or PD-1 treatment targeting the immune system could be used against multiple myeloma. DCs are important in regulating T cell responses against tumors. We therefore determined PDL1 and PDL2 expression on DC populations in bone marrow of patients with plasma cell disorders using multicolour Flow Cytometry. We specifically looked at CD141+ and CD141- myeloid and CD303+ plasmacytoid DC. The majority of plasma cells (PC) and DC subpopulations expressed PDL1, but the proportion of positive PDL1+ cells varied among patients. A correlation between the proportion of PDL1+ PC and CD141+ mDC was found, suggesting both cell types could down-regulate the anti-tumor T cell response.

SUBMITTER: Sponaas AM

PROVIDER: S-EPMC4596870 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

PDL1 Expression on Plasma and Dendritic Cells in Myeloma Bone Marrow Suggests Benefit of Targeted anti PD1-PDL1 Therapy.

Sponaas Anne-Marit AM Moharrami Neda Nejati NN Feyzi Emadoldin E Standal Therese T Holth Rustad Even E Waage Anders A Sundan Anders A

PloS one 20151007 10

In this study we set out to investigate whether anti PDL1 or PD-1 treatment targeting the immune system could be used against multiple myeloma. DCs are important in regulating T cell responses against tumors. We therefore determined PDL1 and PDL2 expression on DC populations in bone marrow of patients with plasma cell disorders using multicolour Flow Cytometry. We specifically looked at CD141+ and CD141- myeloid and CD303+ plasmacytoid DC. The majority of plasma cells (PC) and DC subpopulations ...[more]

PMID: 26444869

Similar Datasets

Explore association of genes in PDL1/PD1 pathway to radiotherapy survival benefit based on interaction model strategy.

Project description:PurposeTo explore the association of genes in "PD-L1 expression and PD-1 check point pathway in cancer" to radiotherapy survival benefit.Methods and materialsGene expression data and clinical information of cancers were downloaded from TCGA. Radiotherapy survival benefit was defined based on interaction model. Fast backward multivariate Cox regression was performed using stacking multiple interpolation data to identify radio-sensitive (RS) genes.ResultsAmong the 73 genes in PD-L1/PD-1 pathway, we identified 24 RS genes in BRCA data set, 25 RS genes in STAD data set and 20 RS genes in HNSC data set, with some crossover genes. Theoretically, there are two types of RS genes. The expression level of Type I RS genes did not affect patients' overall survival (OS), but when receiving radiotherapy, patients with different expression level of Type I RS genes had varied survival benefit. Oppositely, Type II RS genes affected patients' OS. And when receiving radiotherapy, those with lower OS could benefit a lot. Type II RS genes in BRCA had strong positive correlation and closely biological interactions. When performing cluster analysis using these related Type II RS genes, patients could be divided into RS group and non-RS group in BRCA and METABRIC data sets.ConclusionsOur study explored potential radio-sensitive biomarkers of several main cancer types in an important tumor immune checkpoint pathway and revealed a strong association between this pathway and radiotherapy survival benefit. New types of RS genes could be identified based on expanded definition to RS genes.

| S-EPMC8600865 | biostudies-literature

Targeted Approaches to Inhibit Sialylation of Multiple Myeloma in the Bone Marrow Microenvironment.

Project description:Aberrant glycosylation modulates different aspects of tumor biology, and it has long been recognized as a hallmark of cancer. Among the different forms of glycosylation, sialylation, the addition of sialic acid to underlying oligosaccharides, is often dysregulated in cancer. Increased expression of sialylated glycans has been observed in many types of cancer, including multiple myeloma, and often correlates with aggressive metastatic behavior. Myeloma, a cancer of plasma cells, develops in the bone marrow, and colonizes multiple sites of the skeleton including the skull. In myeloma, the bone marrow represents an essential niche where the malignant cells are nurtured by the microenvironment and protected from chemotherapy. Here, we discuss the role of hypersialylation in the metastatic process focusing on multiple myeloma. In particular, we examine how increased sialylation modulates homing of malignant plasma cells into the bone marrow by regulating the activity of molecules important in bone marrow cellular trafficking including selectins and integrins. We also propose that inhibiting sialylation may represent a new therapeutic strategy to overcome bone marrow-mediated chemotherapy resistance and describe different targeted approaches to specifically deliver sialylation inhibitors to the bone marrow microenvironment.

| S-EPMC6787837 | biostudies-literature

Neuronally expressed PDL1, not PD1, suppresses acute nociception.

Project description:PDL1 is a protein that induces immunosuppression by binding to PD1 expressed on immune cells. In line with historical studies, we found that membrane-bound PD1 expression was largely restricted to immune cells; PD1 was not detectable at either the mRNA or protein level in peripheral neurons using single neuron qPCR, immunolabeling and flow cytometry. However, we observed widespread expression of PDL1 in both sensory and sympathetic neurons that could have important implications for patients receiving immunotherapies targeting this pathway that include unexpected autonomic and sensory related effects. While signaling pathways downstream of PD1 are well established, little to no information is available regarding the intracellular signaling downstream of membrane-bound PDL1 (also known as reverse signaling). Here, we administered soluble PD1 to engage neuronally expressed PDL1 and found that PD1 significantly reduced nocifensive behaviors evoked by algogenic capsaicin. We used calcium imaging to examine the underlying neural mechanism of this reduction and found that exogenous PD1 diminished TRPV1-dependent calcium transients in dissociated sensory neurons. Furthermore, we observed a reduction in membrane expression of TRPV1 following administration of PD1. Exogenous PD1 had no effect on pain-related behaviors in sensory neuron specific PDL1 knockout mice. These data indicate that neuronal PDL1 activation is sufficient to modulate sensitivity to noxious stimuli and as such, may be an important homeostatic mechanism for regulating acute nociception.

| S-EPMC10343937 | biostudies-literature

The prognostic significance of polyclonal bone marrow plasma cells in patients with relapsing multiple myeloma.

Project description:Prior studies have revealed that the presence of increasing number of polyclonal plasma cells (pPCs) in the bone marrow (BM) are associated with better outcomes in newly diagnosed multiple myeloma (MM) patients. This effect has not been studied in patients with MM at the time of disease relapse. We determined the prognostic value of depletion of pPCs in the BM by 7-color multiparameter flow cytometry in a series of 174 relapsing MM patients. The time to next therapy (TTNT) in those with <5% pPCs was 9.4 months versus 13.9 months in those with ?5% pPCs (P?=?.0091). The median overall survival (OS) in those with <5% pPCs was 21.4 months, while the median OS was not reached in those patients with ?5% pPCs (P?=?.019). Of the 109 patients with standard risk cytogenetics, the median OS of those with <5% pPCs was 28.4 months, while the median OS was not reached in those with ?5% pPCs (P?=?.033). As such, <5% pPCs in the BM appears to have prognostic utility in identifying a subset of relapsing MM patients, even with standard-risk cytogenetics, who have a particularly adverse outcome.

| S-EPMC5546938 | biostudies-literature

DNA Barcoding Reveals Habitual Clonal Dominance of Myeloma Plasma Cells in the Bone Marrow Microenvironment.

Project description:Multiple myeloma (MM) is a hematological malignancy resulting from the uncontrolled proliferation of antibody-producing plasma cells in the bone marrow. At diagnosis, independent plasma cell tumors are found throughout the skeleton. The recirculation of mutant plasma cells from the initial lesion and their recolonization of distant marrow sites are thought to occur by a process similar to solid tumor metastasis. However, the efficiency of this bone marrow homing process and the proportion of disseminated cells that actively divide and contribute to new tumor growth in MM are both unknown. We used the C57BL/KaLwRij mouse model of myeloma, lentiviral-mediated DNA barcoding of 5TGM1 myeloma cells, and next-generation sequencing to investigate the relative efficiency of plasma cell migration to, and growth within, the bone marrow. This approach revealed three major findings: firstly, establishment of metastasis within the bone marrow was extremely inefficient, with approximately 0.01% of circulating myeloma cells becoming resident long term in the bone marrow of each long bone; secondly, the individual cells of each metastasis exhibited marked differences in their proliferative fates, with the majority of final tumor burden within a bone being attributable to the progeny of between 1 and 8 cells; and, thirdly, the proliferative fate of individual clonal plasma cells differed at each bone marrow site in which the cells "landed." These findings suggest that individual myeloma plasma cells are subjected to vastly different selection pressures within the bone marrow microenvironment, highlighting the importance of niche-driven factors, which determine the disease course and outcome.

| S-EPMC5678743 | biostudies-literature

PD1 is expressed on exhausted T cells as well as virus specific memory CD8+ T cells in the bone marrow of myeloma patients.

Project description:Characterization of CD8+ T cells in the tumor microenvironment (TME) is important to predict responses to checkpoint therapy. The TME in multiple myeloma is the bone marrow, which also is an immune organ where immune responses are generated and memory cells stored. The presence of T cells with other specificities than the tumor in the bone marrow may affect the search for biomarkers to predict responses to immunotherapy in myeloma. Here, we found similar proportions of PD1+ CD8+ T cells and similar levels of PD1 expression on CD8+ T cells in the bone marrow of myeloma patients and healthy controls. PD1 expression on CD8+ T cells did not correlate with tumor load suggesting that at least some of the PD1+ CD8+ T cells were specific for non-myeloma antigens. Indeed, PD1+ EBV-specific CD8+ T cells were detected it the bone marrow of patients. Terminal effectors (Teff), effector memory (Tem) and central memory (Tcm) cells as well as exhausted T cells were all found in the myeloma bone marrow. However, myeloma patients had more terminal effectors and fewer memory cells than healthy controls suggesting that the tumor generate an immune response against myeloma cells in the bone marrow. The presence of CD8 EOMEShigh Tbetlow T cells with intermediate levels of PD1 in myeloma patients suggests that T cell types, that are known to be responsive to checkpoint therapy, are found at the tumor site.

| S-EPMC6112830 | biostudies-other

The advantages of PD1 activating chimeric receptor (PD1-ACR) engineered lymphocytes for PDL1(+) cancer therapy.

Project description:Tumors exploit immunoregulatory checkpoints to attenuate T cell responses as a means of circumventing immunologic rejection. By activating the inhibitory costimulatory pathway of Programmed Death 1 (PD1)/PDL1 which provides tumor cells an escape mechanism from immune surveillance, Programmed Death Ligand1 (PDL1)(+) tumors hamper activated tumor-specific T cell functions and render them functionally exhausted. To overcome the inhibitory costimulatory effects of PDL1 on the adoptively transferred T cells, we sought to convert PD1 to a T cell costimulatory receptor by exchanging its transmembrane and cytoplasmic tail with CD28 and 4-1BB signaling domains (PD1-CD28-4-1BB, PD1-ACR), anticipating the genetically modified effector T lymphocytes expressing PD1-ACR would exhibit enhanced functional attributes. And the results showed that PD1-ACR expressed T cells retained the ability to bind PDL1, resulting in T cell activation as evidenced by the elevated activity of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), the augmentation of cytokine secretion and the increased proliferative capacity. Moreover, when systemically administered in the mouse model of glioblastoma metastases, PD1-ACR T cells localized at the area of U87 invasive tumor, which results in suppressed tumor growth and enhanced survival of mice with established U87 glioblastoma. Together, these data demonstrated that PD1-ACR has a high potential to serve as a novel strategy to overcome PDL1 mediated immunosuppression of T cells for cancer therapy.

| S-EPMC4448187 | biostudies-literature

Targeted Disruption of Bone Marrow Stromal Cell-Derived Gremlin1 Limits Multiple Myeloma Disease Progression In Vivo.

Project description:In most instances, multiple myeloma (MM) plasma cells (PCs) are reliant on factors made by cells of the bone marrow (BM) stroma for their survival and growth. To date, the nature and cellular composition of the BM tumor microenvironment and the critical factors which drive tumor progression remain imprecisely defined. Our studies show that Gremlin1 (Grem1), a highly conserved protein, which is abundantly secreted by a subset of BM mesenchymal stromal cells, plays a critical role in MM disease development. Analysis of human and mouse BM stromal samples by quantitative PCR showed that GREM1/Grem1 expression was significantly higher in the MM tumor-bearing cohorts compared to healthy controls (p < 0.05, Mann-Whitney test). Additionally, BM-stromal cells cultured with 5TGM1 MM PC line expressed significantly higher levels of Grem1, compared to stromal cells alone (p < 0.01, t-test), suggesting that MM PCs promote increased Grem1 expression in stromal cells. Furthermore, the proliferation of 5TGM1 MM PCs was found to be significantly increased when co-cultured with Grem1-overexpressing stromal cells (p < 0.01, t-test). To examine the role of Grem1 in MM disease in vivo, we utilized the 5TGM1/KaLwRij mouse model of MM. Our studies showed that, compared to immunoglobulin G (IgG) control antibody-treated mice, mice treated with an anti-Grem1 neutralizing antibody had a decrease in MM tumor burden of up to 81.2% (p < 0.05, two-way ANOVA). The studies presented here demonstrate, for the first time, a novel positive feedback loop between MM PCs and BM stroma, and that inhibiting this vicious cycle with a neutralizing antibody can dramatically reduce tumor burden in a preclinical mouse model of MM.

| S-EPMC7464474 | biostudies-literature

Resistance Mechanisms of Anti-PD1/PDL1 Therapy in Solid Tumors.

Project description:In cancer-immunity cycle, the immune checkpoint PD1 and its ligand PDL1 act as accomplices to help tumors resist to immunity-induced apoptosis and promote tumor progression. Immunotherapy targeting PD1/PDL1 axis can effectively block its pro-tumor activity. Anti-PD1/PDL1 therapy has achieved great success in the past decade. However, only a subset of patients showed clinical responses. Most of the patients can not benefit from anti-PD1/PDL1 therapy. Furthermore, a large group of responders would develop acquired resistance after initial responses. Therefore, understanding the mechanisms of resistance is necessary for improving anti-PD1/PDL1 efficacy. Currently, researchers have identified primary resistance mechanisms which include insufficient tumor immunogenicity, disfunction of MHCs, irreversible T cell exhaustion, primary resistance to IFN-? signaling, and immunosuppressive microenvironment. Some oncogenic signaling pathways also contribute to the primary resistance. Under the pressure applied by anti-PD1/PDL1 therapy, tumors experience immunoediting and preserve beneficial mutations, upregulate the compensatory inhibitory signaling and induce re-exhaustion of T cells, all of which may attenuate the durability of the therapy. Here we explore the underlying mechanisms in detail, review biomarkers that help identifying responders among patients and discuss the strategies that may relieve the anti-PD1/PDL1 resistance.

| S-EPMC7385189 | biostudies-literature

Immunotherapy for Soft Tissue Sarcomas: Anti-PD1/PDL1 and Beyond.

Project description:Sarcomas gather a heterogeneous group of mesenchymal malignant tumors including more than 150 different subtypes. Most of them represent aggressive tumors with poor prognosis at the advanced stage, despite the better molecular characterization of these tumors and the development of molecular-driven therapeutic strategies. During the last decade, immunotherapy has been developed to treat advanced cancers, mainly thanks to immune checkpoint inhibitors (ICI) such as anti-PD1/PDL1 and later to adoptive immune cell therapies. In this review, we aim to summarize the state of the art of immunotherapy in soft tissue sarcomas (STS). Overall, the clinical trials of ICI that included a wide diversity of STS subtypes reported limited efficacy with some outlying responders. Both emerging biomarkers are of interest in selecting good candidates and in the development of combination therapies. Finally, the recent breakthroughs of innovative adoptive therapies in STS seem highly promising.

| S-EPMC10046205 | 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