B7-H4 expression associates with cancer progression and predicts patient's survival in human esophageal squamous cell carcinoma

Institute of Medical Biotechnology, Medical College of Suzhou University, 708 Renmin Road, Suzhou, Jiangsu, China.
Cancer Immunology and Immunotherapy (Impact Factor: 3.94). 07/2011; 60(7):1047-55. DOI: 10.1007/s00262-011-1017-3
Source: PubMed


A retrospective cohort study including 112 patients suffering from esophageal squamous cell carcinoma (ESCC) was performed to investigate the expression of B7-H4 in ESCC and determine its association with patient's clinicopathological parameters and survival. Expression levels of B7-H4 on tumor cells and densities of tumor infiltrating lymphocytes (TILs) in the surgical specimens of ESCC tissues were characterized using immunohistochemical assays. Uni- and multivariate analyses were performed to evaluate the prognostic value of B7-H4 expression levels and densities of TILs in tumor sections. Positive B7-H4 immunostaining was observed in 107 of 112 (95.5%) of ESCC tissue sections. We further divided all patients into two major subgroups, a lower B7-H4 expression group with 46 patients and a higher B7-H4 expression group with 66 patients. We found that expression levels of B7-H4 on tumor cells were significantly correlated with patient's gender (P = 0.0288), distant metastasis (P = 0.0500), and TNM stage (P = 0.0258). Moreover, tumor cell B7-H4 expression was inversely correlated with densities of CD3(+) T cells in tumor nest (P = 0.0424) and CD8(+) T cells in tumor stroma (P = 0.0229). The overall survival rate of the patients with higher B7-H4 expression was significantly worse than that of the patients with lower B7-H4 expression (P = 0.0105, Hazard Ratio: 1.854, 95%CI:1.152-2.902). Markers of cell-mediated immune responses such as CD3, CD8, and T-bet were associated with better patient survival. The present study demonstrated that B7-H4 expression in human ESCC is associated with cancer progression, reduced tumor immunosurveillance and worse patient outcomes. B7-H4 can serve as a novel prognostic predictor for human ESCC and a potential target for the immune therapy against this malignancy.

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    • "In renal cell carcinoma (Krambeck et al., 2006), patients with tumors expressing B7x are three times more likely to die of cancer compared to patients lacking B7x. In esophageal squamous cell carcinoma, expression levels of B7x on tumor cells are significantly correlated with distant metastasis, tumor stage and worse survival and are inversely correlated with densities of CD3 T cells in tumor nest and CD8 T cells in tumor stroma (Chen et al., 2011). The overexpression of B7x by so many types of human cancers suggests that this pathway may be exploited as an important immune-evasion mechanism. "
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    ABSTRACT: B7x (B7-H4 or B7S1) is a member of the B7 family that can inhibit T cell function. B7x protein is absent in most normal human tissues and immune cells, but it is overexpressed in human cancers and often correlates with negative clinical outcome. The expression pattern and function of B7x suggest that it may be a potent immunosuppressive pathway in human cancers. Here, we determined the crystal structure of the human B7x immunoglobulin variable (IgV) domain at 1.59 Å resolution and mapped the epitopes recognized by monoclonal antibodies. We developed an in vivo system to screen therapeutic monoclonal antibodies against B7x and found that the clone 1H3 significantly inhibited growth of B7x-expressing tumors in vivo via multiple mechanisms. Furthermore, the surviving mice given 1H3 treatment were resistant to tumor rechallenge. Our data suggest that targeting B7x on tumors is a promising cancer immunotherapy and humanized 1H3 may be efficacious for immunotherapy of human cancers. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
    Cell Reports 11/2014; 9(3):1089-98. DOI:10.1016/j.celrep.2014.09.053 · 8.36 Impact Factor
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    • "Constitutive B7-H4 protein expression can be detected in many cancers such as ovarian, breast and melanoma cancer (4, 6-8). Furthermore, overexpression of B7-H4 protein on cancer cells in some of these malignancies is associated with adverse clinical and pathologic features, including constitutional symptoms, tumor necrosis, and advanced tumor size, stage, and so on (8, 9). Otherwise, downregulation of B7-H4 has been showed to enhance T cell proliferation, decrease apoptosis, stimulate cell cycle progression and elevate cytokine production (10). "
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    ABSTRACT: B7-H4 is a member of B7 family of co-inhibitory molecules and B7-H4 protein is found to be overexpressed in many human cancers and which is usually associated with poor survival. In this study, we developed a therapeutic vaccine made from a fusion protein composed of a tetanus toxoid (TT) T-helper cell epitope and human B7-H4IgV domain (TT-rhB7-H4IgV). We investigated the anti-tumor effect of the TT-rhB7-H4IgV vaccine in BALB/c mice and SP2/0 myeloma growth was significantly suppressed in mice. The TT-rhB7-H4IgV vaccine induced high-titer specific antibodies in mice. Further, the antibodies induced by TT-rhB7-H4IgV vaccine were capable of depleting SP2/0 cells through complement-dependent cytotoxicity (CDC) in vitro. On the other hand, the poor cellular immune response was irrelevant to the therapeutic efficacy. These results indicate that the recombinant TT-rhB7-H4IgV vaccine might be a useful candidate of immunotherapy for the treatment of some tumors associated with abnormal expression of B7-H4.
    BMB reports 12/2013; 47(7). DOI:10.5483/BMBRep.2014.47.7.168 · 2.60 Impact Factor
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    • "The distribution of T cell subpopulations differs substantially between patients with and without cancer, increasingly so at more advanced stages of disease and in those patients who have undergone treatment. Heavily treated patients show a relative shrinkage of the naïve and central memory T cell populations but with increased proliferation and differentiation in the direction of effector memory T cells, a state described as T cell exhaustion [12]. "
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    ABSTRACT: Although great effort is being expended in the development of cancer immunotherapies, it is surprising that global lymphopenia and its various dimensions are not being systematically assessed in cancer patients. The incident pathologies associated with various immunosuppressed conditions such as those found in HIV infection have taught us that measuring various T cell populations including CD4 provides the clinician with a reliable measure for gauging the risk of cancer and opportunistic infections. Importantly, recent data emphasize the key link between lymphocyte T cell counts and overall survival in cancer patients receiving chemotherapy. Treatment of immunocompromised patients with interleukin-7 (IL-7), a critical growth and homeostatic factor for T cells, has been shown to produce a compelling profile of T cell reconstitution. The clinical results of this investigational therapy confirm data obtained from numerous preclinical studies and demonstrate the long-term stability of this immune reconstitution, not only on CD4 but also on CD8 T cells, involving recent thymic emigrants as well as naive, memory, and central memory T cells. Furthermore, IL-7 therapy also contributes to restoration of a broadened diversity of the T cell repertoire as well as to migration of these cells to lymph nodes and tissues. All these properties support the initiation of new clinical studies aimed at reconstituting the immune system of cancer patients before or immediately after chemotherapy in order to demonstrate a potentially profound increase in overall survival.
    Targeted Oncology 03/2012; 7(1):55-68. DOI:10.1007/s11523-012-0210-4 · 4.00 Impact Factor
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