Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3.

ABSTRACT: The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation. We also discuss their roles in important pathological states such as cancers, autoimmune diseases, transplantation, and infection. Various immunotherapeutical approaches are emerging including antagonistic monoclonal antibodies and agonistic fusion proteins to inhibit or potentiate these molecules and pathways in cancers and autoimmune diseases.

SUBMITTER: Janakiram M

PROVIDER: S-EPMC5338461 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

The third group of the B7-CD28 immune checkpoint family: HHLA2, TMIGD2, B7x, and B7-H3.

Janakiram Murali M Shah Urvi A UA Liu Weifeng W Zhao Aimin A Schoenberg Mark P MP Zang Xingxing X

Immunological reviews 20170301 1

The B7-CD28 family of ligands and receptors play important roles in T-cell co-stimulation and co-inhibition. Phylogenetically they can be divided into three groups. The recent discovery of the new molecules (B7-H3 [CD276], B7x [B7-H4/B7S1], and HHLA2 [B7H7/B7-H5]/TMIGD2 [IGPR-1/CD28H]) of the group III has expanded therapeutic possibilities for the treatment of human diseases. In this review, we describe the discovery, structure, and function of B7-H3, B7x, HHLA2, and TMIGD2 in immune regulation ...[more]

PMID: 28258693

Similar Datasets

Structure and cancer immunotherapy of the B7 family member B7x.

Project description:B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 Å resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers.

| S-EPMC4250833 | biostudies-literature

B7 family checkpoint regulators in immune regulation and disease.

Project description:Fine-tuning the immune response and maintaining tolerance to self-antigens involves a complex network of co-stimulatory and co-inhibitory molecules. The recent FDA approval of ipilimumab, a monoclonal antibody blocking cytotoxic T lymphocyte antigen (CTLA)-4, demonstrates the impact of checkpoint regulators in disease. This is reinforced by ongoing clinical trials targeting not only CTLA-4, but also the programmed death (PD)-1 and B7-H4 pathways in various disease states. Recently, two new B7 family inhibitory ligands, V-domain Ig suppressor of T cell activation (VISTA) and B7-H6 were identified. Here, we review recent understanding of B7 family members and their concerted regulation of the immune response to either self or foreign pathogens. We also discuss clinical developments in targeting these pathways in different disease settings, and introduce VISTA as a putative therapeutic target.

| S-EPMC3821798 | biostudies-literature

B7x: a widely expressed B7 family member that inhibits T cell activation.

Project description:B7 family proteins provide costimulatory signals that regulate T cell responses. Here we report the third set of B7 family-related T cell inhibitory molecules with the identification of a homolog of the B7 family, B7x. It is expressed in immune cells, nonlymphoid tissues, and some tumor cell lines. B7x inhibits cell-cycle progression, proliferation, and cytokine production of both CD4+ and CD8+ T cells. B7x binds a receptor that is expressed on activated, but not resting T cells that is distinct from known CD28 family members. Its receptor may be a recently identified inhibitory molecule, B and T lymphocyte attenuator. These studies identify a costimulatory pathway that may have a unique function in downregulation of tissue-specific autoimmunity and antitumor responses.

| S-EPMC193571 | biostudies-literature

B7-H7 (HHLA2) inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling.

Project description:Modulation of T-cell responses has played a key role in treating cancers and autoimmune diseases. Therefore, understanding how different receptors on T cells impact functional outcomes is crucial. The influence of B7-H7 (HHLA2) and CD28H (TMIGD2) on T-cell activation remains controversial. Here we examined global transcriptomic changes in human T cells induced by B7-H7. Stimulation through TCR with OKT3 and B7-H7 resulted in modest fold changes in the expression of select genes; however, these fold changes were significantly lower than those induced by OKT3 and B7-1 stimulation. The transcriptional changes induced by OKT3 and B7-H7 were insufficient to provide functional stimulation as measured by evaluating T-cell proliferation and cytokine production. Interestingly, B7-H7 was coinhibitory when simultaneously combined with TCR and CD28 stimulation. This inhibitory activity was comparable to that observed with PD-L1. Finally, in physiological assays using T cells and APCs, blockade of B7-H7 enhanced T-cell activation and proliferation, demonstrating that this ligand acts as a break signal. Our work defines that the transcriptomic changes induced by B7-H7 are insufficient to support full costimulation with TCR signaling and, instead, B7-H7 inhibits T-cell activation and proliferation in the presence of TCR and CD28 signaling.

| S-EPMC8166953 | biostudies-literature

Inhibition of the B7-H3 immune checkpoint limits tumor growth by enhancing cytotoxic lymphocyte function.

Project description:The interaction between tumor and the immune system is still poorly understood. Significant clinical responses have been achieved in cancer patients treated with antibodies against the CTLA4 and PD-1/PD-L1 checkpoints; however, only a small portion of patients responded to the therapies, indicating a need to explore additional co-inhibitory molecules for cancer treatment. B7-H3, a member of the B7 superfamily, was previously shown by us to inhibit T-cell activation and autoimmunity. In this study, we have analyzed the function of B7-H3 in tumor immunity. Expression of B7-H3 was found in multiple tumor lines, tumor-infiltrating dendritic cells, and macrophages. B7-H3-deficient mice or mice treated with an antagonistic antibody to B7-H3 showed reduced growth of multiple tumors, which depended on NK and CD8+ T cells. With a putative receptor expressed by cytotoxic lymphocytes, B7-H3 inhibited their activation, and its deficiency resulted in increased cytotoxic lymphocyte function in tumor-bearing mice. Combining blockades of B7-H3 and PD-1 resulted in further enhanced therapeutic control of late-stage tumors. Taken together, our results indicate that the B7-H3 checkpoint may serve as a novel target for immunotherapy against cancer.

| S-EPMC5539354 | biostudies-literature

Coinhibitory Pathways in the B7-CD28 Ligand-Receptor Family.

Project description:Immune responses need to be controlled for optimal protective immunity and tolerance. Coinhibitory pathways in the B7-CD28 family provide critical inhibitory signals that regulate immune homeostasis and defense and protect tissue integrity. These coinhibitory signals limit the strength and duration of immune responses, thereby curbing immune-mediated tissue damage, regulating resolution of inflammation, and maintaining tolerance to prevent autoimmunity. Tumors and microbes that cause chronic infections can exploit these coinhibitory pathways to establish an immunosuppressive microenvironment, hindering their eradication. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer, autoimmune and infectious diseases, and transplant rejection. In this review we discuss the current knowledge of the mechanisms underlying the coinhibitory functions of pathways in the B7-CD28 family, the diverse functional consequences of these inhibitory signals on immune responses, and the overlapping and unique functions of these key immunoregulatory pathways.

| S-EPMC4905708 | biostudies-literature

The B7x Immune Checkpoint Pathway: From Discovery to Clinical Trial.

Project description:B7x (B7 homolog x, also known as B7-H4, B7S1, and VTCN1) was discovered by ourselves and others in 2003 as the seventh member of the B7 family. It is an inhibitory immune checkpoint of great significance to human disease. Tissue-expressed B7x minimizes autoimmune and inflammatory responses. It is overexpressed in a broad spectrum of human cancers, where it suppresses antitumor immunity. Further, B7x and PD-L1 tend to have mutually exclusive expression in cancer cells. Therapeutics targeting B7x are effective in animal models of cancers and autoimmune disorders, and early-phase clinical trials are underway to determine the efficacy and safety of targeting B7x in human diseases. It took 15 years moving from the discovery of B7x to clinical trials. Further studies will be necessary to identify its receptors, reveal its physiological functions in organs, and combine therapies targeting B7x with other treatments.

| S-EPMC6907741 | biostudies-literature

Structure and T cell inhibition properties of B7 family member, B7-H3.

Project description:T cell activity is controlled by a combination of antigen-dependent signaling through the T cell receptor and a set of auxiliary signals delivered through antigen-independent interactions, including the recognition of the B7 family of ligands. B7-H3 is a recently identified B7 family member that is strongly overexpressed in a range of cancers and correlates with poor prognosis. We report the crystal structure of murine B7-H3 at a 3 Å resolution, which provides a model for the organization of the IgV and IgC domains within the ectodomain. We demonstrate that B7-H3 inhibits T cell proliferation and show that the FG loop of the IgV domain plays a critical role in this function. B7-H3 crystallized as an unusual dimer arising from the exchange of the G strands in the IgV domains of partner molecules. This arrangement, in combination with previous reports, highlights the dynamic nature and plasticity of the immunoglobulin fold.

| S-EPMC3998375 | biostudies-literature

Expression, Clinical Significance, and Receptor Identification of the Newest B7 Family Member HHLA2 Protein.

Project description:HHLA2 (B7H7/B7-H5/B7y) is a newly identified B7 family member that regulates human T-cell functions. However, its protein expression in human organs and significance in human diseases are unknown. The objective of this study was to analyze HHLA2 protein expression in normal human tissues and cancers, as well as its prognostic significance, to explore mechanisms regulating HHLA2 expression, and to identify candidate HHLA2 receptors.An immunohistochemistry protocol and a flow cytometry assay with newly generated monoclonal antibodies were developed to examine HHLA2 protein. HHLA2 gene copy-number variation was analyzed from cancer genomic data. The combination of bioinformatics analysis and immunologic approaches was established to explore HHLA2 receptors.HHLA2 protein was detected in trophoblastic cells of the placenta and the epithelium of gut, kidney, gallbladder, and breast, but not in most other organs. In contrast, HHLA2 protein was widely expressed in human cancers from the breast, lung, thyroid, melanoma, pancreas, ovary, liver, bladder, colon, prostate, kidney, and esophagus. In a cohort of 50 patients with stage I-III triple-negative breast cancer, 56% of patients had aberrant expression of HHLA2 on their tumors, and high HHLA2 expression was significantly associated with regional lymph node metastasis and stage. The Cancer Genome Atlas revealed that HHLA2 copy-number gains were present in 29% of basal breast cancers, providing a potential mechanism for increased HHLA2 protein expression in breast cancer. Finally, Transmembrane and Immunoglobulin Domain Containing 2 (TMIGD2) was identified as one of the receptors for HHLA2.Wide expression of HHLA2 in human malignancies, together with its association with poor prognostic factors and its T-cell coinhibitory capability, suggests that the HHLA2 pathway represents a novel immunosuppressive mechanism within the tumor microenvironment and an attractive target for human cancer therapy.

| S-EPMC4433806 | biostudies-literature

Identification of PD-L2, B7-H3 and CTLA-4 immune checkpoint proteins in genetic subtypes of meningioma.

Project description:Meningioma is the most common brain tumor in adults. Surgical resection remains the primary treatment. No chemotherapy exists. However, gene mutations now could explain ~ 80% of meningioma and targeted therapies based on these are being investigated. Furthermore, with the recent discovery of PD-L1 in malignant meningioma, clinical trials using immunotherapy have commenced. Here, we report for the first time the expression profiles of immune checkpoint proteins PD-L2, B7-H3 and CTLA-4 in meningioma and their association to common gene mutations. PD-L2 and B7-H3 expression was significantly greater than all immune checkpoint proteins studied, and particularly elevated in patients with gene mutations affecting the PI3K/AKT/mTOR pathway. CTLA-4 expressing CD3+ lymphocytes were observed in atypical and malignant meningioma and tumors harboring a PIK3CA or SMO mutation. These results identify novel targets for immunotherapy irrespective of grade and distinguish potential patient populations based on genetic classification for stratification into checkpoint inhibitor clinical trials.

| S-EPMC6287792 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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