Overexpression of B7-H3 Is Associated With Poor Prognosis in Laryngeal Cancer

The immune checkpoint molecule, B7-H3, which belongs to the B7 family, has been shown to be overexpressed in various cancers. Its role in tumors is not well defined, and many studies suggest that it is associated with poor clinical outcomes. The effect of B7-H3 on laryngeal cancer has not been reported. This study investigated the expression of B7-H3 in laryngeal squamous cell carcinoma (LSCC), and its relationship with clinicopathological factors and prognosis of LSCC patients. The gene expression quantification data and clinical data of LSCC retrieved from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database were analyzed to determine the diagnostic and prognostic roles of B7-H3. Quantitative real-time polymerase chain reaction (qRT-PCR) was then performed to determine the gene expression level of B7-H3 between LSCC tissues and paired normal adjacent tissues. In addition, TCGA RNA-seq data was analyzed to evaluate the expression level of B7 family genes. Next, the protein expression of B7-H3 and CD8 in LSCC was determined using immunohistochemistry and immunofluorescence. qRT-PCR results showed that the expression level of B7-H3 mRNA was significantly higher in LSCC tissues than in adjacent normal tissues. Similar results were obtained from the TCGA analysis. The expression of B7-H3 was significantly associated with T stage, lymph node metastasis, and pathological tumor node metastasis (TNM) stage, and it was also an independent factor influencing the overall survival time (OS) of patients with LSCC. In addition, B7-H3 was negatively correlated with CD8+T cells. These results show that B7-H3 is upregulated in LSCC. Therefore, B7-H3 may serve as a biomarker of poor prognosis and a promising therapeutic target in LSCC.

Administration of anti-ERMAP antibody ameliorates Alzheimer’s disease in mice

Background Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder and characterized by progressive loss of memory and cognitive functions, which are associated with amyloid-beta (Aβ) plaques. Immune cells play an important role in the clearance of Aβ deposits. Immune responses are regulated by immune regulators in which the B7 family members play a crucial role. We have recently identified erythroid membrane-associated protein (ERMAP) as a novel B7 family-related immune regulator and shown that ERMAP protein affects T cell and macrophage functions. Methods We produced a monoclonal antibody (mAb) against ERMAP protein and then determined the ability of the mAb to affect cognitive performance and AD pathology in mice. Results We have shown that the anti-ERMAP mAb neutralizes the T cell inhibitory activity of ERMAP and enhances macrophages to phagocytose Aβ in vitro. Administration of the mAb into AD mice improves cognitive performance and reduces Aβ plaque load in the brain. This is related to increased proportion of T cells, especially IFNγ-producing T cells, in the spleen and the choroid plexus (CP), enhanced expression of immune cell trafficking molecules in the CP, and increased migration of monocyte-derived macrophages into the brain. Furthermore, the production of anti-Aβ antibodies in the serum and the macrophage phagocytosis of Aβ are enhanced in the anti-ERMAP mAb-treated AD mice. Conclusions Our results suggest that manipulating the ERMAP pathway has the potential to provide a novel approach to treat AD patients.

B7–H3 regulates osteoclast differentiation via type I interferon-dependent IDO induction

While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7–H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7–H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7–H3 is highly expressed in mature osteoclasts and that B7–H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7–H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7–H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7–H3, inhibition of B7–H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7–H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN–IDO signaling as its downstream mechanism.

The Positive and Negative Immunoregulatory Role of B7 Family: Promising Novel Targets in Gastric Cancer Treatment

Gastric cancer (GC), with a heterogeneous nature, is the third leading cause of death worldwide. Over the past few decades, stable reductions in the incidence of GC have been observed. However, due to the poor response to common treatments and late diagnosis, this cancer is still considered one of the lethal cancers. Emerging methods such as immunotherapy with immune checkpoint inhibitors (ICIs) have transformed the landscape of treatment for GC patients. There are presently eleven known members of the B7 family as immune checkpoint molecules: B7-1 (CD80), B7-2 (CD86), B7-H1 (PD-L1, CD274), B7-DC (PDCD1LG2, PD-L2, CD273), B7-H2 (B7RP1, ICOS-L, CD275), B7-H3 (CD276), B7-H4 (B7x, B7S1, Vtcn1), B7-H5 (VISTA, Gi24, DD1α, Dies1 SISP1), B7-H6 (NCR3LG1), B7-H7 (HHLA2), and Ig-like domain-containing receptor 2 (ILDR2). Interaction of the B7 family of immune-regulatory ligands with the corresponding receptors resulted in the induction and inhibition of T cell responses by sending co-stimulatory and co-inhibitory signals, respectively. Manipulation of the signals provided by the B7 family has significant potential in the management of GC.

B7 Family Molecule VSIG4 Regulates Intestinal Anti-Enterohemorrhagic Escherichia coli Immunity by Altering Gut Flora Diversity

As an essential member of the B7 family, V-set and immunoglobulin domain-containing 4 (VSIG4) is expressed explicitly in tissue-resident macrophages (TRMs) and plays an essential role in maintaining the homeostasis of the environmental immune system. Here, we demonstrate that gene-targeted VSIG4-deficient mice infected with Enterohemorrhagic Escherichia coli (EHEC) display reduced bacterial burden. To reveal the role of VSIG4 in the fight against EHEC infection, we collected mice feces and used high-throughput 16S rRNA gene amplicons to detect changes in the flora. A total of 657330 sequences were sequenced on the PacBio platform, with an average length of 1498 bp. We found that VSIG4 deficiency could alter the gut microbiota by increasing diversity and shifting community composition. In particular, G_Akkermansia and G_Oscillo spiraceae increased significantly. These findings expand upon a prior observation that VSIG4 deficiency reduced EHEC colonization by changing the gut microbiota diversity and shifting community composition.

RANKL-Induced Btn2a2 – A T Cell Immunomodulatory Molecule – During Osteoclast Differentiation Fine-Tunes Bone Resorption

Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory molecules. Despite recent advances in the understanding on butyrophilins’ role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts. We found that expression of Btn2a2 on monocytes and pre-osteoclasts is upregulated by the receptor activator of nuclear factor κ-B ligand (RANKL), an essential protein required for osteoclast formation. Interestingly, in Btn2a2-deficient osteoclasts, typical osteoclast marker genes (Nfatc1, cathepsin K, TRAP, and RANK) were downregulated following RANKL stimulation. In vitro osteoclast assays resulted in decreased TRAP positive osteoclast numbers in Btn2a2-deficient cells. However, Btn2a2-deficient osteoclasts revealed abnormal fusion processes shown by their increased size. In vivo steady state µCT and histological analysis of bone architecture in complete Btn2a2-deficient mice showed differences in bone parameters further highlighting the fine-tuning effect of BTN2a2. Moreover, in rheumatoid arthritis patients and experimental arthritis, we detected significantly decreased serum levels of the secreted soluble Btn2a2 protein. Taken together, we identified the involvement of the immunomodulatory molecule Btn2a2 in osteoclast differentiation with potential future implications in basic and translational osteoimmunology.

B7-H3/CD276: An Emerging Cancer Immunotherapy

Immunotherapy aiming at suppressing tumor development by relying on modifying or strengthening the immune system prevails among cancer treatments and points out a new direction for cancer therapy. B7 homolog 3 protein (B7-H3, also known as CD276), a newly identified immunoregulatory protein member of the B7 family, is an attractive and promising target for cancer immunotherapy because it is overexpressed in tumor tissues while showing limited expression in normal tissues and participating in tumor microenvironment (TME) shaping and development. Thus far, numerous B7-H3-based immunotherapy strategies have demonstrated potent antitumor activity and acceptable safety profiles in preclinical models. Herein, we present the expression and biological function of B7-H3 in distinct cancer and normal cells, as well as B7-H3-mediated signal pathways in cancer cells and B7-H3-based tumor immunotherapy strategies. This review provides a comprehensive overview that encompasses B7-H3’s role in TME to its potential as a target in cancer immunotherapy.