Expression Of B7 Family Molecules Research Articles

Prognostic Value of Programmed Death Ligand-1 in Discriminating Patients With Lymph Node-Negative, p53-Wild-Type, or Low-BRCA1/2-Expression Pancreatic Ductal Adenocarcinoma.

Alterations in the tumor microenvironment affect the response to immunotherapy and are associated with clinical outcomes. However, the role of B7 family checkpoint molecules in pancreatic ductal adenocarcinoma (PDAC) remains unclear. To investigate the expression of programmed death ligand-1 (PD-L1), B7 homolog 3 (B7-H3), and B7 homolog 4 (B7-H4) and the association of these molecules with pathologic features, DNA damage repair (DDR) molecules, immune infiltrates, and survival in PDAC. The expression of B7 family molecules, densities of immune cells, and DDR status were evaluated by using immunohistochemical assays in tissue microarrays. Positive PD-L1 expression on tumor cells (TCs) and stromal cells (SCs) was observed in 30.3% (80 of 264) and 20.5% (54 of 264) of patients, respectively, whereas B7-H3 showed positivity in 81.3% (195 of 240) and 87.9% (211 of 240) of patients, respectively. B7-H4 was detected exclusively in tumor cells, with a positivity rate of 76.0% (193 of 254). PD-L1 on TCs was an independent predictor of worse disease-free survival, whereas B7-H3 on TCs was an independent factor of improved survival. The prognostic significance of PD-L1 was more discriminative in lymph node-negative, p53-wild-type, and low-BRCA1/2-expression tumors. B7-H3 on SCs was negatively correlated with CD45RO T cells, whereas PD-L1 on SCs was related to high densities of CD3, CD4, CD8, CD45RO, and Foxp3 T cells and B7-H4 was more common in tumors with a low CD8 status. We identified B7 family checkpoint molecules as potentially prognostic indicators, combined with different DDR molecular statuses and complex immune infiltrates, in PDAC.

Expression and clinical significance of negative costimulatory molecules B7-H1, B7-H3 and B7-H4 in the process of colorectal cancer’s evolution

Background: We made investigations on the expression of negative costimulatory molecules B7-H1, B7-H3, B7-H4 in lesions at various stages of human colorectal cancer (CRC) evolution. We also analyzed the relevance between its expression in CRC and pathological factors in clinic and patient survival time. We finally made a result that we can ensure the clinical significance of B7-H3, B7-H4 expression and the relationship between the B7 family molecules expression. Methods: All stages of CRC were collected, including polyps, adenomas, high-grade neoplasms, and colorectal carcinomas. There were 98 cases of resected CRC tissue, 30 cases of polyps, 30 cases of adenomas, and 25 cases of high-grade neoplasia. Then analysis the expression of three negative costimulatory molecules in all stages of colorectal tissue expression patterns, flow cytometry CD3+ T lymphocytes B7 family molecules to explore the potential value of their expression. Results: The expression of B7 family molecules in 30 cases of polyps, 30 cases of adenomas, 25 cases of high-grade neoplasia, and 98 cases of CRC tissues revealed that the B7-H1 and B7-H3 expression quantity was found in polyps, adenomas, high-grade neoplasms, as well as they were highly expressed in cancerous tissues. B7-H4 was only expressed in cancerous tissues. In the TNM stage of tumor progression, three negative costimulatory molecules were mainly expressed in the cytoplasm of tumor cells. In CRC in lymphocytes B7-H4 expression was related to patient age, mucinous adenocarcinoma, and lymph node metastasis. Survival analysis showed in CRC it was statistically significant that that the expression of B7-H3 and the survival rate of patients. We found that 92.9% of CRC patients expressed B7 family negative costimulatory molecules in varying degrees, and the prognosis and co-expression of B7 family negative co-stimulatory molecules were negatively correlated. Conclusions: Costimulatory molecules B7-H1, B7-H3 were expressed on the early stage of CRC development. The amount of CD3+ T lymphocyte infiltration in CRC was positively correlated with the survival of patients. They are the earliest molecules to participate in the progress of CRC developing in B7 family negative molecules. This suggests that B7-H1 and B7-H3 are involved in rectal carcinoma at the junction, as well as it is essential throughout the entire evolutionary process. However, it is in CRC tissues that B7-H4 only get expressed, and different expression patterns may have different clinical significances.

Comprehensive molecular profiling of the B7 family in gastrointestinal cancer.

B7 family has been identified as co-stimulatory or co-inhibitory molecules on T-cell response and plays an important role in tumour mortality and malignancy. In this study, the expression pattern of B7 family in gastrointestinal (GI) cancer was examined. Its upstream regulating mechanism, downstream targets and association with clinical parameters were also studied. The expression level of B7 members was analysed by FIREHOUSE. The gene mutation, DNA methylation, association with clinical parameters and downstream network of B7 members were analysed in cBioportal. The mutation frequency was analysed by Catalogue of Somatic Mutations in Cancer (COSMIC) analysis. The phylogenetic tree was constructed in MEGA7. The interaction protein domain analysis was performed by Pfam 31.0. Differential expression of B7 family molecules was detected in different kinds of GI cancer. High-frequency gene alteration was found in tumour samples. There was negative correlation of promoter methylation and mRNA expression of B7 family members in tumour samples, suggesting the epigenetic basis of B7 family gene deregulation in GI cancer. The overexpression of B7-H1 in pancreatic cancer, B7-H5 in oesophageal cancer and B7-H6 in liver cancer were significantly associated with worse overall survival. Finally, by network analysis, we identified some potential interacting proteins for B7-1/2 and B7-H1/DC. Overall, our study suggested that B7 member deregulation was strongly involved in GI cancer tumorigenesis.

Dynamic expression of B7 family molecules on hematopoietic stem cells

Dynamic expression of B7 family molecules on hematopoietic stem cells

Ocena ekspresji wybranych molekuł z rodziny B7 na powierzchni dojrzałych komórek dendrytycznych u chorych na raka krtani

B7-H1, B7-H2 and B7-H4 molecules play various roles in the adaptive immune system and are broadly expressed on many cells, especially those localized in cancer tissue. The aim of the study was to assess the surface expression of B7-H1, B7-H2 and B7-H4 molecules on the mature dendritic cells (DC) generated from peripheral blood monocytes of laryngeal cancer patients and healthy donors. Material and methodsForty-four male patients treated surgically for squamous cell carcinoma of the larynx were included in the study. Peripheral blood from twelve healthy male donors was used as a control. Mononuclear cells were separated from all individuals by density gradient centrifugation, incubated with anti-CD14 microbeads, and passed through MACS separation columns. The CD14 positive cell population was used to prepare monocyte derived DC. Laryngeal cancer tissue was obtained from patients during surgical treatment and homogenized to prepare tumor cell lysates for further stimulation. We evaluated with the use of flow cytometry method the percentage of cells with an expression and mean fluorescent intensity (MFI) of surface markers, such as: CD83, B7-H1, B7-H2, B7-H4. ResultsOur study revealed that the percentage of mature dendritic cells, stimulated with autologous tumor cell lysates, with the expression of B7-H1 molecule in patients was lower than in healthy donors (61.81±25.58% vs 93.02±4.63%, p=0.007). In laryngeal cancer patients, the percentage of CD83+/B7-H2+ cells was higher than in healthy individuals (18.32±10.74% vs 2.89±0.43%, p=0.019). ConclusionsThere is a relation between the presence of laryngeal cancer and the expression of B7 family molecules.

Expression and Function of B7 Family Molecules on Blasts of Patients with Myelodysplastic Syndromes

Optimal activation of T cells requires second costimulatory signals together with the first signal delivered by engagement of the T‑cell receptor with the peptide‑MHC complex on antigen presenting cells (APCs such as macrophages B cells and dendritic cells. The interaction between B7 molecules i.e. B7‑1 (CD80B7‑2 (CD86 on APCs and CD28CTLA‑4 molecules on T cells is the most well‑characterized costimulatory signal pathway and is thought to be crucial in eliciting an antitumor immune response. Recently several new members of the B7 family B7‑H1 B7‑H2 B7‑H3 and B7‑H4 have been identified. B7‑H1 inhibits the proliferation of T cells through a counterreceptor programmed death 1 (PD‑1 and delivers a stimulatory signal to T cells through an as yet unidentified counterreceptor other than PD‑1 12 . We detected the expression of B7‑H1 on activated T cells and some tumor cells such as those from melanoma lung ovarian and colon cancers and showed that B7‑H1 on tumor cells suppresses antitumor immunity by inhibiting the proliferation of tumor‑specific cytotoxic T lymphocytes (CTLs 3 . Consistent with these results patients with renal cell carcinoma and breast cancer expressing B7‑H1 have been reported to have a poor prognosis. B7‑H2 is expressed on professional APCs and tumor cells such as those from glioma and gastric carcinoma. The counterreceptor of B7‑H2 inducible costimulator (ICOS is expressed on activated T cells. The B7‑H2‑ICOS signal induces T cells to proliferate and to secrete both Th1 and Th2 cytokines such as interleukin (IL‑4 and interferon‑γ but not the potent Th1 cytokine IL‑2. Furthermore the B7‑H2‑ICOS signal induces IL‑10 production. When we investigated the expression of B7 family molecules in hematological malignancies B7‑H1 or B7‑H2 or both were detected in leukemia myeloma and lymphoma cells. We have recently reported that cells from many patients with acute myeloid leukemia (AML express B7‑2 and B7‑H2 molecules and that B7‑1 and B7‑H1 expression is rare 4 . Patients with B7‑H2‑positive AML had significantly shorter survival times. Furthermore B7‑ 2 expression was associated with hyperleukocytosis. Consistent with these findings AML cells expressing B7‑2 and B7‑H2 induced allogeneic CD4 + T cells to proliferate and secrete IL‑4 and IL‑10 in vitro effects that were

P-13 Expression of B7 family molecules on blasts of patients with myelodysplastic syndromes (MDS) and de novo acute myeloid leukemia (AML)

P-13 Expression of B7 family molecules on blasts of patients with myelodysplastic syndromes (MDS) and de novo acute myeloid leukemia (AML)

Generation of Anti-Leukemia Reactive T-Cells by Costimulation with Established B-ALL Cell Lines Expressing Costimulatory Molecules.

Activated B cells expressing the B7 family of molecules are efficient antigen presenting cells. However, most of B-lineage leukemia cells do not fullfill these criteria, having lost their immunostimulatory potential both in vivo and in vitro. We have established 3 human B-ALL(L3) cell-lines (BA-25, BA-78 and BA91) which in comparison with an established pre-B-ALL cell line (BA-127) and other patients-derived pre-B-ALL blast cells do express the costimulatory molecules CD80 and/or CD86, as well as other critical costimulatory molecules for T-cell stimulation such as: CD40, ICAM-I, LFA-3 and CD72. Flow cytometry analysis demonstrate that these B-ALL cells have an activated B-cell phenotype (CD19+, CD20+, CD22+, CD38+, CD71+, CD75+, DR+, HLA-class-I and HLA-class-II). Chromosomal translocations consistent with B-ALL (L3) were determined in BA-25 [t(2;28)(p12;q24)], BA-78 [t(8;14)(q24,q32)] and BA-91 [t(8;14) (q24,q32)]. No EBV DNA sequence was found in these B-ALL cell lines by Southern blot analysis with a probe for EBV genome. In mixted lymphocyte reaction (MLR) assay, Allogeneic T cells were stimulated by BA-25 and BA-91 cells at a B : T cells ratios of 1/30, 1/100, 1/300 and 1/1000. The BA-25 and BA-91 demonstrated 1-2 logs higher ccpm than the control pre-B-ALL cells (BA-127) which with no expression of B7 family molecules. The dose response curves for the B-cell mixture ratio display a linear pattern between 217-213 log2 ccpm. To determine T cell stimulation potential of the B-ALL cells, we co-cultured allogeneic PBMC with irradiated (3,000 Rad x-ray) BA-25 cells at 30:1 effector/stimulator ratio and achieved a 3–4 fold expansion of T cells after one round 7-day stimulation. Stimulation of allogeneic PBMC with BA-25 elicited proliferation of the T-cells and lysis of BA-25 as an target in a 4h Cr51 release assay, demonstrating BA-25 as an antigen presenting cell. Studies also show that the BA-25 cells could stimulate allo-cytolytic reactions by CTLs against other human leukemic target cells which lack these molecules and fail to stimulate T cell responses by themselves. Thus, BA-25 and other similar lines may prove useful for the provision of costimulatory signal needed to stimulate T-cell response against leukemias lacking these molecules.