B7h6

Understanding the mechanisms that regulate T cell immunity is critical for the development of effective therapies for diseases associated with T cell dysfunction, including autoimmune diseases, chronic infections, and cancer. Co-inhibitory "checkpoint molecules," such as programmed cell death protein-1, balance excessive or prolonged immune activation by T cell-intrinsic signaling. Here, by screening for mediators of natural killer (NK) cell recognition on T cells, we identified the immunoglobulin superfamily ligand B7H6 to be highly expressed by activated T cells, including patient-infused CD19-targeting chimeric antigen receptor (CAR) T cells...

BACKGROUND: Non-muscle-invasive bladder cancer (NMIBC) is treated with transurethral resection of bladder tumor (TURBT) followed by intravesical instillation of chemotherapy or Bacillus Calmette-Guérin therapy. However, these treatments have a high recurrence rate and side effects, emphasizing the need for alternative instillations. Previously, we revealed that expanded allogeneic human natural killer (NK) cells from peripheral blood are a promising cellular therapy for prostate cancer...

Glioblastoma multiforme (GBM) is among the malignant brain tumors of the central nervous system (CNS). The survival of this disease is about 14 months after diagnosis. To date, temozolomide is known as first-line therapy for glioma. Drug resistance and severe side effects against this drug are important obstacles to the effective treatment of this cancer. Small interfering RNA (siRNA) can adjust the expression of several genes and is used as a new method of gene therapy. Recent studies have shown that siRNAs can increase the sensitivity of cancer cells to chemotherapy drugs...

Cutaneous melanoma (CM) is a highly metastatic cancer whose incidence rate is heightening worldwide. B7H6, as one of the co-stimulatory ligands of the B7 family, is expressed in malignant cells, involved in tumorigenesis. This study aimed to investigate the significance of B7H6 in CM cell chemosensitivity and metastatic ability. A375 CM cells were transfected with B7H6-siRNA and treated with dacarbazine individually or combined. The MTT assay to estimate half-maximal inhibitory concentration of dacarbazine and cell viability, the apoptotic induction using Annexin V/PI, cell cycle progression via flow cytometry, and wound healing assay for determining the migration ability of cells and assessing the clonogenic potential of A375 cells were executed...

The NKp30 receptor is one of the three natural cytotoxic receptors reported in NK cells. This receptor is codified by the NCR3 gene, which encodes three isoforms, a consequence of the alternative splicing of exon 4. A greater expression of the three isoforms (A, B, and C), along with low levels of the NKp30 ligand B7H6, has been reported as a positive prognostic factor in different cancer types. Here, in patients with cervical cancer and precursor lesions, we report an altered immune-phenotype, characterized by non-fitness markers, that correlated with increased disease stage, from CIN 1 to FIGO IV...

Induction of heme oxygenase 1 (HO-1) favors immune-escape in BRAFV600 melanoma cells treated with Vemurafenib/PLX4032 under standard cell culture conditions. However, the oxygen tension under standard culture conditions (~18 kPa O2 ) is significantly higher than the physiological oxygen levels encountered in vivo. In addition, cancer cells in vivo are often modified by hypoxia. In this study, MeOV-1 primary melanoma cells bearing the BRAFV600E mutation, were adapted to either 5 kPa O2 (physiological normoxia) or 1 kPa O2 (hypoxia) and then exposed to 10 μM PLX4032...

Pancreatic cancer (PC), the third leading cause of cancer-related death in the U.S., is frequently found too late to be cured by traditional chemotherapy. Expression of B7 homolog 6 (B7H6), a member of the B7 family of immunoreceptors, has been found in PC and several other cancers. B7H6 is a ligand for cytotoxicity triggering receptor 3 (NKp30), which is expressed on NK cells. Here, we demonstrate that B7H6 can be detected in PC tissues but not normal organs. Its expression in patients associated significantly with tumor differentiation grade and lymphatic metastasis...

B7H6, a stress-induced ligand which binds to the NK cell receptor NKp30, has recently emerged as a promising candidate for immunotherapy due to its tumor-specific expression on a broad array of human tumors. NKp30 can function as a chimeric antigen receptor (CAR) extracellular domain but exhibits weak binding with a fast on and off rate to B7H6 compared to the TZ47 anti-B7H6 single-chain variable fragment (scFv). Here, directed evolution using yeast display was employed to isolate novel NKp30 variants that bind to B7H6 with higher affinity compared to the native receptor but retain its fast association and dissociation profile...

Natural killer (NK) cells play major roles in innate immunity against viruses and cancer. Natural killer receptors (NKR) expressed by NK cells recognize foreign- or self-ligands on infected and transformed cells as well as healthy cells. NKR genes are the most rapidly evolving loci in vertebrates, and it is generally difficult to detect orthologues in different taxa. The unique exception is NKp30, an activating NKR in mammals that binds to the self-ligand B7H6. The NKp30-encoding gene, NCR3, has been found in most vertebrates including sharks, the oldest vertebrates with human-type adaptive immunity...

BACKGROUND: Although great progress has been made in treatment regimens, cervical cancer remains as one of the most common cancer in women worldwide. Studies focusing on molecules that regulate carcinogenesis may provide potential therapeutic strategies for cervical cancer. B7-H6, an activating immunoligand expressed by several tumor cells, is known to activate NK cell-mediated cytotoxicity once engaged with its natural receptor NKp30. However, the opposite, that is, the effects in the tumor cell triggered by B7-H6 after interacting with NKp30 has not yet been well explored...

Herein, we report the development of sandwich type Surface Enhanced Raman Spectroscopy (SERS) immunosensor modified to be zwitterionic for the detection of soluble B7-H6 biomarker in blood serum from cervical cancer patients. Anti-fouling capture SERS substrate of biosensor based on gold (Au) thin film was modified with a self-assembled monolayer of zwitterionic l-cysteine to combat serum fouling and was then conjugated with NKp30 receptor protein to capture the B7-H6 biomarker in blood serum. The SERS nanoprobe based on spiky gold nanoparticles (AuNPs) was functionalized with ATP reporter molecule, that is stable at a wide range of pH, making the SERS signal reliable in complex media...

De novo cancer-targeting immunostimulatory peptides have been designed and developed as synthetic antibody mimics. A series of bifunctional peptides incorporating NKp30-binding and NK-cell-activating domains were synthesized as linear dimers and then extended into branching trimeric peptides by the incorporation of GRP78-targeting and tumor-cell-binding sequences. A selected trimeric peptide from this small set of peptides displayed binding capabilities on GRP78+ HepG2 and A549 target cells. Cell binding diminished in the presence of an anti-GRP78 peptide blocker, thus suggesting GRP78-binding dependence...

BACKGROUND: Targeted therapies and immunotherapies are first-line treatments for patients with advanced melanoma. Serine-threonine protein kinase B-RAF (BRAF) and mitogen-activated protein kinase (MEK) inhibition leads to a 70% response rate in patients with advanced melanoma with a BRAFV600E / K mutation. However, acquired resistance occurs in the majority of patients, leading to relapse. Immunotherapies that activate immune cytotoxic effectors induce long-lasting responses in 30% of patients...

Gastric cancer (GC) is one of the most commonly diagnosed malignancies and, unfortunately, still has a high mortality rate. Recent research points to CAR-T immunotherapy as a promising treatment for this disease. Using genetically engineered T cells designed to target a previously selected antigen, researchers are able to harness the natural anti-tumor activity of T cells. For therapy to be successful, however, it is essential to choose antigens that are present on tumor cells but not on healthy cells. In this review, we present an overview of the most important targets for CAR-T therapy in the context of GC, including their biologic function and therapeutic application...

The B7 family member, B7H6, is a ligand for the natural killer cell receptor NKp30. B7H6 is hardly expressed on normal tissues, but undergoes upregulation on different types of tumors, implicating it as an attractive target for cancer immunotherapy. The molecular mechanisms that control B7H6 expression are poorly understood. We report that in contrast to other NK cell ligands, endoplasmic reticulum (ER) stress upregulates B7H6 mRNA levels and surface expression. B7H6 induction by ER stress requires protein kinase R-like ER kinase (PERK), one of the three canonical sensors of the unfolded protein response...

NK cells kill cancer cells and infected cells upon activation by cell surface receptors. Human NKp30 is an activating receptor expressed by all mature NK cells. The B7 family member B7H6 has been identified as one ligand for NKp30. Several alternative ligands have also been reported, and the field remains unsettled. To this end, we have identified full-length functional B7H6 orthologs in rat and cattle, demonstrated by phylogenetic analysis and transfection experiments. In cell-cell contact-dependent assays, chimeric NKp30 reporter cells responded strongly to B7H6 in rat and cattle...

The B7 family, the most common family of secondary signaling molecules, consists of eight cell-surface proteins, which regulate the T-cell mediated immune response by delivering co-inhibitory or co-stimulatory signals through their corresponding ligands. Among them, natural killer cell cytotoxicity receptor 3 ligand 1 (NCR3LG1, also known as B7H6) has been reported as a new member, and is involved in tumor progression of various types of human cancer. However, the role of B7H6 in triple-negative breast cancer (TNBC) remains unknown...

Chimeric antigen receptor (CAR) therapy has shown promise against B cell malignancies in the clinic. However, limited success in patients with solid tumors has prompted the development of new CAR strategies. In this study, a B7H6-specific CAR was combined with different variants of T-bet, a transcription factor that acts as the master regulator to induce a Th1 phenotype in CD4+ T cells, to create more effective CAR T cells. Skewing CD4+ CAR T cells into a Th1 improved CAR T cell functional activity while promoting a robust proinflammatory response against B7H6-expressing tumors...

B7H6 is emerging as a promising tumor antigen that is known to be expressed on a wide array of tumors and is reported to stimulate anti-tumor responses from the immune system. As such, B7H6 presents a good target for tumor-specific immunotherapies. B7H6-specific chimeric antigen receptors (CAR) based on a murine antibody showed successful targeting and elimination of tumors expressing B7H6. However, mouse single chain variable fragments (scFvs) have the potential to induce host anti-CAR responses that may limit efficacy, so human scFvs specific for B7H6 were selected by yeast surface display...

B7H6, an endogenous ligand expressed on tumor cell surfaces, triggers NKp30-mediated activation of human NK cells. In contrast, the release of soluble B7H6 has been proposed as a novel mechanism by which tumors might evade NK cell-mediated recognition. Since NK cells are critical for the maintenance of early pregnancy, it is not illogical that soluble B7H6 might also be an important factor in directing NK cell activity during normal pregnancy. Thus, this study was focused on the characterization of soluble B7H6 during the development of normal pregnancy...