Genomic Organization and Expression Analysis of B7-H4, an Immune Inhibitory Molecule of the B7 Family

Choi, In Taek; Zhu, Gefeng; Sica, Gabriel L.; Strome, Scott E.; Cheville, John C.; Lau, Julie S.; Zhu, Yuwen; Flies, Dallas B.; Tamada, Koji; Chen, Lieping

doi:10.4049/jimmunol.171.9.4650

Cited by 230 publications

(243 citation statements)

References 18 publications

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“…Recent reports, however, indicate focal and infrequent protein expression in certain somatic tissues, including distal convoluted tubules of the kidney, ductal and acinar cells of the pancreas, endometrial glands, transitional epithelia of the ureter and bladder, bronchial epithelium of the lung, and columnar epithelium of the gallbladder (5). Additionally, B7-H4 has been found to be aberrantly expressed at high levels in human serous, endometrioid, and clear cell ovarian carcinoma; ductal and lobular breast cancer; and lung cancer (5,6,21). This overexpression of B7-H4 by malignant tissues may render B7-H4 a particularly useful target for facilitating antitumoral immunotherapeutic responses.…”

Section: Discussionmentioning

confidence: 99%

“…Although B7-H4 mRNA has been noted in a number of nonlymphoid organs (3), it was originally believed that protein expression was restricted to activated lymphoid cells (4,6,7). Recent reports, however, indicate focal and infrequent protein expression in certain somatic tissues, including distal convoluted tubules of the kidney, ductal and acinar cells of the pancreas, endometrial glands, transitional epithelia of the ureter and bladder, bronchial epithelium of the lung, and columnar epithelium of the gallbladder (5).…”

Section: Discussionmentioning

confidence: 99%

“…Weak or sporadic expression of B7-H4 has also been observed in some peripheral tissues, presumably surveyed from human autopsy specimens or tissues that were removed because of pathologic conditions not directly involving the organ being examined (5). Human cancers of the lung, breast, and ovary have also been shown to aberrantly overexpress the B7-H4 protein ligand (4,6,7).…”

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B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

Krambeck¹,

Thompson²,

Dong³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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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.B7-H1 ͉ costimulation ͉ tumor biomarker ͉ immunotherapy ͉ kidney neoplasms

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

Krambeck¹,

Thompson²,

Dong³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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279

251

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“…However, B7x protein expression seems to be more restricted compared with B7-H3. Despite mRNA expression in various human tissues, immunohistochemistry (IHC) for B7x fails to reveal detectable protein expression in any healthy human organs (23). In stark contrast, aberrant expression of B7x has been observed in cancers of the breast (22,24), lung (16), ovary (22,25), uterus (26), and kidney (27).…”

mentioning

confidence: 99%

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome

Zang

Thompson²,

Al‐Ahmadie³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

345

327

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B7-H3 and B7x are recently discovered members of the B7-CD28 family thought to dampen peripheral immune responses via negative costimulation. We evaluated their potential expression in human prostate cancer using a large cohort of patients with 7 years of follow-up. We identified 823 patients with tissue available treated with radical prostatectomy between 1985 and 2003. Immunohistochemistry was performed on tissue microarray sections using anti-B7-H3 and -B7x. The percentage and intensity of immunoreactivity by tumor cells were blindly evaluated by two urological pathologists, and outcome analyses were conducted. Both B7-H3 and B7x were highly expressed; 93% and 99% of tumors had aberrant expression, respectively. The median percentage of tumor cells staining positive was 80% for each molecule. Strong intensity for B7-H3 and B7x was noted in 212 (26%) and 120 (15%) patients, respectively. Patients with strong intensity for B7-H3 and B7x were significantly more likely to have disease spread at time of surgery (P < 0.001 and P ‫؍‬ 0.005, respectively). Additionally, patients with strong intensity for B7-H3 and B7x were at significantly increased risk of clinical cancer recurrence (P < 0.001 and P ‫؍‬ 0.005) and cancer-specific death (P ‫؍‬ 0.004 and P ‫؍‬ 0.04, respectively). To our knowledge, we present the largest investigation of B7 family molecules in a human malignancy and a previously undescribed evaluation of B7x in prostate cancer. B7-H3 and B7x are abundantly expressed in prostate cancer and associated with disease spread and poor outcome. Given the proposed immune-inhibitory mechanisms of B7-H3 and B7x, these molecules represent attractive targets for therapeutic manipulation in prostate cancer.immune tolerance ͉ prostatic neoplasms ͉ treatment outcome ͉ biological tumor markers

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“…The same study showed that B7-H4-Fc proteins suppressed the expansion of bone marrow-derived CD11b + Gr-1 + neutrophil progenitors in vitro. Apart from the immune system, B7-H4 transcripts and proteins are overexpressed in breast cancer (11)(12)(13), ovarian cancer (6,(13)(14)(15)(16), lung cancer (6,17,18), and many other solid tumors (19)(20)(21)(22)(23)(24)(25) to varying extents. In some cancers, the proportion of B7-H4-positive tumor area and the intensity of B7-H4 immunostaining have been positively correlated with the invasiveness of the tumors, poor prognosis, and mortality (20)(21)(22)(23)(24)(25).…”

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confidence: 99%

Host B7-H4 Regulates Antitumor T Cell Responses through Inhibition of Myeloid-Derived Suppressor Cells in a 4T1 Tumor Transplantation Model

Leung

Suh

2013

The Journal of Immunology

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B7-H4, a member of the B7 family of T cell immunomodulatory proteins, has been shown to inhibit T cell responses and neutrophil expansion during bacterial infections. However, the role of B7-H4 in the immune response during tumor growth has been unclear. In this study, we examined the host immune responses in B7-H4–deficient (knockout [KO]) or sufficient (wild-type [WT]) BALB/cJ mice upon transplantation of murine 4T1 carcinoma cells that had little B7-H4 expression. We reveal that host B7-H4 not only dampens the antitumor Th1 responses, but also inhibits the protumor function of myeloid-derived suppressor cells (MDSC). We observed increased expression of both antitumor immune effectors and protumor MDSC-associated transcripts in 4T1 tumors grown in B7-H4 KO mice compared with those grown in WT hosts. Consistently, MDSCs derived from B7-H4 KO mice suppressed T cell proliferation more potently than their WT counterparts. Although the primary growth of 4T1 tumors in B7-H4 KO hosts was similar to that in WT mice, tumors that had grown in B7-H4 KO hosts grew much slower than those from WT mice when subsequently transplanted into WT hosts. Importantly, this differential tumor growth during the secondary transplantation was abrogated when recipient mice lacked T cells, indicating that the immune environment in B7-H4 KO hosts allowed outgrowth of 4T1 tumors with reduced immune-evasive capacities against T cells. Thus, B7-H4 can inhibit both antitumor T cells and protumor MDSCs, influencing the immune-evasive character of the outgrowing tumors. These factors should be considered if B7-H4 blockade is to be used for cancer immunotherapy.

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Genomic Organization and Expression Analysis of B7-H4, an Immune Inhibitory Molecule of the B7 Family

Cited by 230 publications

References 18 publications

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

B7-H4 expression in renal cell carcinoma and tumor vasculature: Associations with cancer progression and survival

B7-H3 and B7x are highly expressed in human prostate cancer and associated with disease spread and poor outcome

Host B7-H4 Regulates Antitumor T Cell Responses through Inhibition of Myeloid-Derived Suppressor Cells in a 4T1 Tumor Transplantation Model

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