28 research outputs found
B7-H4 gene polymorphisms are associated with sporadic breast cancer in a Chinese Han population
© 2009 Zhang et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licens
B7-H4 Treatment of T Cells Inhibits ERK, JNK, p38, and AKT Activation
B7-H4 is a newly identified B7 homolog that plays an important role in maintaining T-cell homeostasis by inhibiting T-cell proliferation and lymphokine-secretion. In this study, we investigated the signal transduction pathways inhibited by B7-H4 engagement in mouse T cells. We found that treatment of CD3+ T cells with a B7-H4.Ig fusion protein inhibits anti-CD3 elicited T-cell receptor (TCR)/CD28 signaling events, including phosphorylation of the MAP kinases, ERK, p38, and JNK. B7-H4.Ig treatment also inhibited the phosphorylation of AKT kinase and impaired its kinase activity as assessed by the phosphorylation of its endogenous substrate GSK-3. Expression of IL-2 is also reduced by B7-H4. In contrast, the phosphorylation state of the TCR proximal tyrosine kinases ZAP70 and lymphocyte-specific protein tyrosine kinase (LCK) are not affected by B7-H4 ligation. These results indicate that B7-H4 inhibits T-cell proliferation and IL-2 production through interfering with activation of ERK, JNK, and AKT, but not of ZAP70 or LCK
Potential Role of Decoy B7-H4 in the Pathogenesis of Rheumatoid Arthritis: A Mouse Model Informed by Clinical Data
Finding an association between soluble B7-H4 and rheumatoid arthritis severity, Lieping Chen and colleagues use a mouse model to show that the soluble form blocks the inhibitory function of cell-surface B7-H4
Comparison of Expression Profiles in Ovarian Epithelium In Vivo and Ovarian Cancer Identifies Novel Candidate Genes Involved in Disease Pathogenesis
Molecular events leading to epithelial ovarian cancer are poorly understood but
ovulatory hormones and a high number of life-time ovulations with concomitant
proliferation, apoptosis, and inflammation, increases risk. We identified genes
that are regulated during the estrous cycle in murine ovarian surface epithelium
and analysed these profiles to identify genes dysregulated in human ovarian
cancer, using publically available datasets. We identified 338 genes that are
regulated in murine ovarian surface epithelium during the estrous cycle and
dysregulated in ovarian cancer. Six of seven candidates selected for
immunohistochemical validation were expressed in serous ovarian cancer,
inclusion cysts, ovarian surface epithelium and in fallopian tube epithelium.
Most were overexpressed in ovarian cancer compared with ovarian surface
epithelium and/or inclusion cysts (EpCAM, EZH2, BIRC5) although BIRC5 and EZH2
were expressed as highly in fallopian tube epithelium as in ovarian cancer. We
prioritised the 338 genes for those likely to be important for ovarian cancer
development by in silico analyses of copy number aberration and
mutation using publically available datasets and identified genes with
established roles in ovarian cancer as well as novel genes for which we have
evidence for involvement in ovarian cancer. Chromosome segregation emerged as an
important process in which genes from our list of 338 were over-represented
including two (BUB1, NCAPD2) for which there
is evidence of amplification and mutation. NUAK2, upregulated in ovarian surface
epithelium in proestrus and predicted to have a driver mutation in ovarian
cancer, was examined in a larger cohort of serous ovarian cancer where patients
with lower NUAK2 expression had shorter overall survival. In conclusion,
defining genes that are activated in normal epithelium in the course of
ovulation that are also dysregulated in cancer has identified a number of
pathways and novel candidate genes that may contribute to the development of
ovarian cancer
B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival
B7-H4 is a recently described B7 family coregulatory ligand that has been implicated as an inhibitor of T cell-mediated immunity. Although expression of B7-H4 is typically limited to lymphoid cells, aberrant B7-H4 expression has also been reported in several human malignancies. To date, associations of B7-H4 with clinical outcomes for cancer patients are lacking. Therefore, we examined B7-H4 expression in fresh-frozen tumor specimens from 259 renal cell carcinoma (RCC) patients treated with nephrectomy between 2000 and 2003 and performed correlative outcome analyses. We report that 153 (59.1%) RCC tumor specimens exhibited B7-H4 staining and that tumor cell B7-H4 expression was associated with adverse clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and grade. Patients with tumors expressing B7-H4 were also three times more likely to die from RCC compared with patients lacking B7-H4 (risk ratio = 3.05; 95% confidence interval = 1.51–6.14; P = 0.002). Additionally, 211 (81.5%) specimens exhibited tumor vasculature endothelial B7-H4 expression, whereas only 6.5% of normal adjacent renal tissue vessels exhibited endothelial B7-H4 staining. Based on these findings, we conclude that B7-H4 has the potential to be a useful prognostic marker for patients with RCC. In addition, B7-H4 represents a target for attacking tumor cells as well as tumor neovasculature to facilitate immunotherapeutic treatment of RCC tumors. Last, we demonstrate that patients with RCC tumors expressing both B7-H4 and B7-H1 are at an even greater risk of death from RCC
Ultraviolet radiation attenuates thrombospondin 1 expression via PI3K-Akt activation in human keratinocytes
Thrombospondin 1 (TSP1) is an extracellular glycoprotein and a recognized inhibitor of angiogenesis. Recent studies have demonstrated that UV radiation induces an angiogenic switch, by which it alters the balance between pro- and anti-angiogenic factors in the skin. Here we describe the effects of acute UV exposure on TSP1 expression in human skin epidermis, primary keratinocytes and the epidermal cell line HaCaT. We found that protein and mRNA expressions of TSP1 are significantly reduced in human skin in vivo and in keratinocytes in vitro by a single UV exposure. In human skin and keratinocytes, UV exposure induced the phosphorylation of Akt, a downstream target of the PI3K pathways. Specific inhibitors of PI3K, wortmannin and LY294002, completely blocked Akt activation and UV-induced TSP1 downregulation in keratinocytes. We showed that a specific Akt phosphorylation inhibitor and small interfering RNA-mediated Akt depletion were also blocked by UV-induced TSP1 downregulation in keratinocytes. In conclusion, our findings demonstrate that acute UV exposure downregulates TSP1 expression via PI3K-Akt activation in human keratinocytes. These novel findings may help us understand the regulatory mechanisms of UV-induced skin angiogenesis
Isolation and Validation of Anti-B7-H4 scFvs from an Ovarian Cancer scFv Yeast-Display Library.
B7-H4 (VTCN1, B7x, B7s) is an inhibitory modulator of T-cell response implicated in antigen tolerization. As such, B7-H4 is an immune checkpoint of potential therapeutic interest. To generate anti-B7-H4 targeting reagents, we isolated antibodies by differential cell screening of a yeast-display library of recombinant antibodies (scFvs) derived from ovarian cancer patients and we screened for functional scFvs capable to interfere with B7-H4-mediated inhibition of antitumor responses. We found one antibody binding to B7-H4 that could restore antitumor T cell responses. This chapter gives an overview of the methods we developed to isolate a functional anti-B7-H4 antibody fragment