B7-H4 overexpression contributes to poor prognosis and drug-resistance in triple-negative breast cancer

Yang, Chao; Liu, Xinbo; Wang, Li; Kang, Fubiao

doi:10.1186/s12935-018-0597-9

Cited by 37 publications

(37 citation statements)

References 59 publications

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“…Incubated T cells with B7S1-Ig fusion protein in vitro significantly inhibits the proliferation and cytotoxic activity of T cells, by interfering with the activation of ERK, JNK, and AKT (Wang et al, 2012;Wang and Wang, 2020). B7S1 silencing enhanced drug-induced apoptosis by inhibiting the PTEN/ PI3K/AKT pathway in triple-negative breast cancer cells (Wang et al, 2018). Furthermore, blockade of B7S1 downregulated the transcription of CXCL12/CXCR4.…”

Section: Introductionmentioning

confidence: 98%

Phenotypic and Functional Analyses of B7S1 in Ovarian Cancer

Cai

Wang

et al. 2021

Front. Mol. Biosci.

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Background: Although programmed death (PD) ligand 1 (PD-L1)/PD-1 inhibitors show potent and durable antitumor effects in a variety of tumors, their efficacy in patients with OvCa is modest. Thus, additional immunosuppressive mechanisms beyond PD-L1/PD-1 need to be identified.Methods: The mRNA expression profiles of OvCa patients were obtained from The Cancer Genome Atlas (TCGA) database. The expression and clinical characteristics of VTCN1 (encoding B7S1) in OvCa were analyzed. The molecular interaction network, Gene Ontology (GO) analysis and Gene set enrichment analysis (GSEA) were used to functionally annotate and predict signaling pathways of VTCN1 in OvCa. Moreover, 32 treatment-naïve patients with OvCa were recruited to assess B7S1 expression. The cytotoxic immune phenotypes in distinct subgroups were analyzed.Results: B7S1 expression was increased in tumor sections compared with that in normal tissues from OvCa patients at both the mRNA and protein levels. VTCN1 expression was significantly correlated with the mRNA expression levels of several other co-inhibitory immune checkpoints. B7S1 protein was found to be highly expressed in CD45+CD68+ myeloid cells, whereas its putative receptor was expressed in CD8+ tumor-infiltrating lymphocytes (TILs). Furthermore, expression of B7S1 in antigen-presenting cells (APCs) was significantly correlated with the cytolytic function of CD8+ TILs. Functional annotations indicated that VTCN1 was involved in regulating T cell-mediated immune responses and participated in the activation of a variety of classic signaling pathways related to the progression of human cancer.Conclusion: In OvCa, B7S1 was highly expressed and may initiate dysfunction of CD8+ TILs, which could be targeted for cancer immunotherapy.

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Section: Introductionmentioning

confidence: 98%

Phenotypic and Functional Analyses of B7S1 in Ovarian Cancer

Cai

Wang

et al. 2021

Front. Mol. Biosci.

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“…Huang et al showed that the OS rate of patients with higher B7-H4 expression was signi cantly worse than in those with lower expression [18]. Similarly, TNBC patients with B7-H4 overexpression had signi cantly shorter survival and recurrence time than those with low B7-H4 expression [19]. These data suggest that B7-H4 might be a potential negative prognostic indicator.…”

Section: Discussionmentioning

confidence: 99%

Soluble B7-H4 and its association with clinical characteristics and prognosis in patients with early breast cancer

Mach

Hoffmann

Kasimir‐Bauer

et al. 2020

Preprint

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Background: Immunotherapy is a promising area for treatment of breast cancer (BC) that has transformed patient care. Immune checkpoint inhibitors are only effective in a subset of patients, and the identification of biomarkers that predict response to therapy is crucial to increase the rates of responders. B7-H4 is a potentially novel target for cancer therapy.Methods: We examined the association of sB7-H4 with clinical characteristics and prognosis in patients with early BC. Using ELISA, we analyzed sB7-H4 serum concentrations in a total of 572 early BC patients before the onset of therapy, 109 patients (cohort 1) in the neo-adjuvant setting and 463 patients in the adjuvant setting (cohort 2). In cohort 1, measurements were also performed after neo-adjuvant therapy (NACT).Results: In cohort 1, sB7-H4 blood serum concentration was delectable in 27/109 (26%) patients before and in 50/109 (48%) patients after NACT. In cohort 2, the detection rate was only 4% (18/461 patients). In cohort 1, no significant differences between patients, even when stratifying for particular intrinsic subtypes, before and after NACT were observed. No significant chances in sB7-H4 blood serum concentration levels before and after NACT were associated with clinical parameters, prognosis and the risk of recurrence. The median blood serum concentration levels in cohort 2 were significantly higher than in cohort 1 after NACT (p=0.04) but not before NACT. Conclusions: sB7-H4 concentration levels in serum of non-metastatic BC patients are neither associated with prognosis nor with clinical characteristics in the adjuvant and neo-adjuvant setting.

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“…There are multiple mechanisms by which B7-H4 can affect tumor cell biology. Wang et al (34) reported that silencing B7-H4 enhances drug-induced apoptosis by inhibiting the phosphatase and tensin homolog (PTEN)/PI3K/AKT signaling pathway, indicating the role of B7-H4 in chemoresistance and suggesting that it may be an attractive therapeutic target in triple-negative breast cancer. Xie et al (15) demonstrated that B7-H4 induced epithelial-mesenchymal transition, and promoted invasion and metastasis of tumor cells by the activation of the ERK1/2 signaling pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Additionally, it has been reported that B7-H4 is upregulated in several types of cancer ( 28 – 31 ), which suggests that B7-H4 has the potential to be used as a biomarker or therapeutic target for tumors ( 19 , 31 – 33 ). However, other studies revealed that B7-H4 promotes cell proliferation ( 34 , 35 ), invasion and metastasis of tumor cells ( 15 , 35 , 36 ), enhances leukemia-initiating cell differentiation ( 23 ), and is correlated with carcinogenesis and chemoresistance ( 34 , 37 ).…”

Section: Discussionmentioning

confidence: 99%

Overexpression of B7‑H4 promotes renal cell carcinoma progression by recruiting tumor‑associated neutrophils via upregulation of CXCL8

Zhang

Zhao

et al. 2020

Oncol Lett

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The immune checkpoint molecule B7 family member H4 (B7-H4) plays a similar role to programmed death-ligand 1 in tumor immune evasion by regulating T-cell-mediated immune responses. However, besides the role in T-cell immunity, B7-H4 also affects tumor cell biology by promoting tumor cell proliferation, metastasis and angiogenesis. In order to explore the effect of B7-H4 on tumor cell biology, it is necessary to investigate the gene expression profile when B7-H4 is overexpressed. In the present study, 786-O cells were transfected to stably express B7-H4. A microarray technique was subsequently used to screen B7-H4-related differentially expressed genes (DEGs) in B7-H4/786-O cells compared with negative control (NC)/786-O cells. The protein expression of the upregulated DEGs, including non-metastatic cells 5, NME/NM23 family member 5 (NME5), membrane metalloendopeptidase (MME), vascular non-inflammatory molecule 1 (VNN1), matrix metalloproteinase (MMP) 7, tumor necrosis factor, C-X-C motif chemokine ligand (CXCL) 8, CXCL1 and CC motif chemokine ligand (CCL) 2, was investigated using western blotting. Kidney renal papillary cell carcinoma mRNA-sequencing data obtained from The Cancer Genome Atlas revealed that chemokines, including CXCL1/2/3, CXCL8, MMP7 and CCL20, were positively correlated with B7-H4 gene expression. Furthermore, 59 clinical renal cell carcinoma tissues were collected and analyzed by immu-nohistochemical staining. The results revealed the positive correlation of B7-H4 with CCL20 and CXCL8, and validated the DEGs identified in tumor cell lines. 786-O transfectants were inoculated into non-obese diabetic/severe combined immunodeficiency mice, and tumor growth was investigated. B7-H4 overexpression promoted tumor growth and administration of anti-CXCL8 antibody reversed this effect. Furthermore, B7-H4 overexpression increased the number of tumor-infiltrating neutrophils while inhibition of CXCL8 abrogated this effect. These data indicated that recruitment of neutrophils in the tumor microenvironment by CXCL8 serves an important role in the tumor promotion effect of B7-H4. The present study revealed a novel mechanism of B7-H4 in tumor promotion in addition to T cell inhibition.

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B7-H4 overexpression contributes to poor prognosis and drug-resistance in triple-negative breast cancer

Cited by 37 publications

References 59 publications

Phenotypic and Functional Analyses of B7S1 in Ovarian Cancer

Phenotypic and Functional Analyses of B7S1 in Ovarian Cancer

Soluble B7-H4 and its association with clinical characteristics and prognosis in patients with early breast cancer

Overexpression of B7‑H4 promotes renal cell carcinoma progression by recruiting tumor‑associated neutrophils via upregulation of CXCL8

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