Pvrl2

BACKGROUND: Preoperative differentiation of benign and malignant tumor types is critical for providing individualized treatment interventions to improve prognosis of patients with ovarian cancer. High-throughput proteomics analysis of urine samples was performed to identify reliable and non-invasive biomarkers that could effectively discriminate between the two ovarian tumor types. METHODS: In total, 132 urine samples from 73 malignant and 59 benign cases of ovarian carcinoma were divided into C1 (training and test datasets) and C2 (validation dataset) cohorts...

The recent discovery of immune checkpoint inhibitors is a significant milestone in cancer immunotherapy research. However, some patients with primary or adaptive drug resistance might not benefit from the overall therapeutic potential of immunotherapy in oncology. Thus, it is becoming increasingly critical for oncologists to explore the availability of new immune checkpoint inhibitors. An emerging co-inhibitory receptor, CD112R (also called PVRIG), is most commonly expressed on natural killer (NK) and T cells...

Immune checkpoint molecules, also known as cosignaling molecules, are pivotal cell-surface molecules that control immune cell responses by either promoting (costimulatory molecules) or inhibiting (coinhibitory molecules) a signal. These molecules have been studied for many years. The application of immune checkpoint drugs in the clinic provides hope for cancer patients. Recently, the poliovirus receptor (PVR)-like protein cosignaling network, which involves several immune checkpoint receptors, i.e., DNAM-1 (DNAX accessory molecule-1, CD226), TIGIT (T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM)), CD96 (T cell activation, increased late expression (TACLILE)), and CD112R (PVRIG), which interact with their ligands CD155 (PVR/Necl-5), CD112 (PVRL2/nectin-2), CD111 (PVRL1/nectin-1), CD113 (PVRL3/nectin-3), and Nectin4, was discovered...

The inhibitory receptor TIGIT, as well as theectonucleotidases CD39 and CD73 constitute potential exhaustion markers for T cells. Detailed analysis of these markers can shed light into dysregulation of the T-cell response in acute myeloid leukemia (AML) and will help to identify potential therapeutic targets.  The phenotype and expression of transcription factors was assessed on different T-cell populations derived from peripheral blood (PB, n = 38) and bone marrow (BM, n = 43). PB and BM from patients with AML diagnosis, in remission and at relapse were compared with PB from healthy volunteers (HD) ( n = 12) using multiparameter flow cytometry...

Background: Apolipoprotein ( APOE ) ε4 is recognized as an independent risk factor for mild cognitive impairment (MCI). However, not everyone with the ε4 allele develops MCI, suggesting that other susceptibility genes exist. This study aimed to identify MCI susceptibility genes, including BIN1, MC1R, STARD6 , and PVRL2 , in elderly Han Chinese and to verify their association with APOE ε4 allele in MCI onset. Methods: To determine whether polymorphisms in BIN1 (rs6733839, rs7561528), MC1R (rs2228479), STARD6 (rs10164112), and PVRL2 (rs6859) occurred in elderly MCI patients carrying APOE ε4 allele, we carried out a case-control study including 285 MCI patients and 326 healthy controls...

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder. Since the advent of the genome-wide association study (GWAS) we have come to understand much about the genes involved in AD heritability and pathophysiology. Large case-control meta-GWAS studies have increased our ability to prioritize weaker effect alleles, while the recent development of network-based functional prediction has provided a mechanism by which we can use machine learning to reprioritize GWAS hits in the functional context of relevant brain tissues like the hippocampus and amygdala...

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy worldwide, as patients are typically diagnosed at a late stage and eventually develop chemoresistant disease following front-line platinum-taxane based therapy. Only modest results have been achieved with PD-1 based immunotherapy in ovarian cancer patients, despite the fact that immunological responses are observed in EOC patients. Therefore, the goal of this present study was to identify novel immune response genes and cell subsets significantly associated with improved high grade serous ovarian cancer (HGSOC) patient prognosis...

For precision medicine, there is an enormous need to understand the immune evasion mechanism of tumor development, especially when tumor heterogeneity significantly affects the effect of immunotherapy. Recognizing the subtypes of breast cancer based on the immune-related genes helps to understand the immune escape pathways dominated by different subtypes, so as to implement effective treatment measures for different subtypes. For that, we used non-negative matrix factorization and consistent clustering algorithm on The Cancer Genome Atlas RNA-seq breast cancer data and recognized 4 subtypes according to the curated immune-related genes...

This study explored the novel immune checkpoint poliovirus receptor-related immunoglobulin domain-containing (PVRIG) in acute myeloid leukemia (AML). We showed that AML patient blasts consistently expressed the PVRIG ligand (poliovirus receptor-related 2, PVRL2). Furthermore, PVRIG blockade significantly enhanced NK cell killing of PVRL2+, poliovirus receptor (PVR)lo AML cell lines, and significantly increased NK cell activation and degranulation in the context of patient primary AML blasts. However, in AML patient bone marrow, NK cell PVRIG expression levels were not increased...

Pancreatic cancer (PC) is one of the most deadly cancers worldwide. To uncover the unknown novel biomarker used to indicate early diagnosis and prognosis in the molecular therapeutic field of PC is extremely of importance. Accumulative evidences indicated that aberrant expression or activation of immunoinhibitors is a common phenomenon in malignances, and significant associations have been noted between immunoinhibitors and tumorigenesis or progression in a wide range of cancers. However, the expression patterns and exact roles of immunoinhibitors contributing to tumorigenesis and progression of pancreatic cancer (PC) have not yet been elucidated clearly...

Inference of causality between gene expression and complex traits using Mendelian randomization (MR) is confounded by pleiotropy and linkage disequilibrium (LD) of gene-expression quantitative trait loci (eQTL). Here, we propose an MR method, MR-link, that accounts for unobserved pleiotropy and LD by leveraging information from individual-level data, even when only one eQTL variant is present. In simulations, MR-link shows false-positive rates close to expectation (median 0.05) and high power (up to 0.89), outperforming all other tested MR methods and coloc...

Tumors evade immune-mediated recognition through multiple mechanisms of immune escape. On chronic tumor antigen exposure, T cells become dysfunctional/exhausted and upregulate various checkpoint inhibitory receptors (IRs) that limit T cells' survival and function. During the last decade, immunotherapies targeting IRs such as programmed cell death receptor 1 (PD-1) and anticytotoxic T lymphocyte-associated antigen 4 (CTLA-4) have provided ample evidence of clinical benefits in many solid tumors. Beyond CTLA-4 and PD-1, multiple other IRs are also targeted with immune checkpoint blockade in the clinic...

BACKGROUND: Although the human chromosome 19q13 loci are reported to be associated with hyper-LDL-cholesterolemia, the haplotype of single nucleotide polymorphism (SNP) has not been studied. Therefore, the association of the haplotype in 19q13 loci with hyper-LDL-cholesterolemia was determined and their interactions with lifestyles and nutrient intakes were evaluated in 28,445 Koreans aged > 40 years. METHODS: SNPs were selected from 19q13 loci that had an association with hyper-LDL-cholesterolemia with the adjustment of confounders (age, gender, area of residence, and body mass index)...

Human longevity is a complex trait influenced by both genetic and environmental factors, whose interaction is mediated by epigenetic mechanisms like DNA methylation. Here, we generated genome-wide whole-blood methylome data from 267 individuals, of which 71 were long-lived (90-104 years), by applying reduced representation bisulfite sequencing. We followed a stringent two-stage analysis procedure using discovery and replication samples to detect differentially methylated sites (DMSs) between young and long-lived study participants...

BACKGROUND: The etiology of Alzheimer's disease remains poorly understood at the mechanistic level, and genome-wide network-based genetics have the potential to provide new clues of the disease mechanisms. OBJECTIVE: To explore the collective effects of multiple genetic association signals on an AV-45 PET measure, which is a well-known Alzheimer's disease biomarker, by employing a network-assisted strategy. METHOD: First, we took advantage of dense module search algorithm to identify modules enriched by genetic association signals in a protein-protein interaction network...

Alzheimer's disease (AD) is a leading cause of mortality in the elderly. While the coding change of APOE-ε4 is a key risk factor for late-onset AD and has been believed to be the only risk factor in the APOE locus, it does not fully explain the risk effect conferred by the locus. Here, we report the identification of AD causal variants in PVRL2 and APOC1 regions in proximity to APOE and define common risk haplotypes independent of APOE-ε4 coding change. These risk haplotypes are associated with changes of AD-related endophenotypes including cognitive performance, and altered expression of APOE and its nearby genes in the human brain and blood...

Variants associated with modulation of c-reactive protein (CRP) and plasma lipids have been investigated for polygenic overlap with Alzheimer's disease risk variants. We examined pleiotropic genetic effects on cognitive impairment conditioned on genetic variants (SNPs) associated with systemic inflammation as measured by CRP and with plasma lipids using data from the Health and Retirement Study. SNP enrichment was observed for cognitive impairment conditioned on the secondary phenotypes of plasma CRP and lipids...

A limitation to antitumor immunity is the dysfunction of T cells in the tumor microenvironment, in part due to upregulation of coinhibitory receptors such as PD-1. Here, we describe that poliovirus receptor-related immunoglobulin domain protein (PVRIG) acts as a coinhibitory receptor in mice. Murine PVRIG interacted weakly with poliovirus receptor (PVR) but bound poliovirus receptor-like 2 (PVRL2) strongly, making the latter its principal ligand. As in humans, murine NK and NKT cells constitutively expressed PVRIG...

Although checkpoint inhibitors that block CTLA-4 and PD-1 have improved cancer immunotherapies, targeting additional checkpoint receptors may be required to broaden patient response to immunotherapy. PVRIG is a coinhibitory receptor of the DNAM/TIGIT/CD96 nectin family that binds to PVRL2. We report that antagonism of PVRIG and TIGIT, but not CD96, increased CD8+ T-cell cytokine production and cytotoxic activity. The inhibitory effect of PVRL2 was mediated by PVRIG and not TIGIT, demonstrating that the PVRIG-PVRL2 pathway is a nonredundant signaling node...

After allogeneic stem cell transplantation (alloSCT), several immune checkpoints play an important role in the antileukemic immune response in the bone marrow (BM) microenvironment. However, immune checkpoint expression levels in the BM have not been reported after alloSCT in patients with acute myeloid leukemia (AML). We investigated the clinical impact of immune checkpoint expression in BM samples after alloSCT for AML. Higher expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) was associated with a decreased incidence of acute graft-versus-host disease (P = ...