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Review
. 2017 Mar;276(1):40-51.
doi: 10.1111/imr.12530.

Potential targeting of B7-H4 for the treatment of cancer

Joseph R Podojil  1 , Stephen D Miller  1
Affiliations
Review

Potential targeting of B7-H4 for the treatment of cancer

Joseph R Podojil et al. Immunol Rev. 2017 Mar.

Abstract

Observations noting the presence of white blood cell infiltrates within tumors date back more than a century, however the cellular and molecular mechanisms regulating tumor immunity continue to be elucidated. The recent successful use of monoclonal antibodies to block immune regulatory pathways to enhance tumor-specific immune responses for the treatment of cancer has encouraged the identification of additional immune regulatory receptor/ligand pathways. Over the past several years, a growing body of data has identified B7-H4 (VTCN1/B7x/B7S1) as a potential therapeutic target for the treatment of cancer. The potential clinical significance of B7-H4 is supported by the high levels of B7-H4 expression found in numerous tumor tissues and correlation of the level of expression on tumor cells with adverse clinical and pathologic features, including tumor aggressiveness. The biological activity of B7-H4 has been associated with decreased inflammatory CD4+ T-cell responses and a correlation between B7-H4-expressing tumor-associated macrophages and FoxP3+ regulatory T cells (Tregs) within the tumor microenvironment. Since B7-H4 is expressed on tumor cells and tumor-associated macrophages in various cancer types, therapeutic blockade of B7-H4 could favorably alter the tumor microenvironment allowing for antigen-specific clearance tumor cells. The present review highlights the therapeutic potential of targeting B7-H4.

Keywords: B7-H4; B7-H4 receptor; CD4+ T cell; cancer; co-stimulatory/co-inhibitory molecule; regulatory T cell.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors do not have any conflicts of interest regarding this work.

Figures

FIGURE 1
FIGURE 1
Blockade of B7-H4: B7-H4R interaction. Inflammatory cytokines and other cytokines/factors within the tumor microenvironment, such as IL-2, IL-6, IL-10, IFN-α, IFN-γ, TNF-α, and hypoxia, have been shown to induce B7-H4 expression on both tumor cells and monocytes/ macrophages. Additionally, activated T cells have been shown to express the B7-H4R via specific binding of B7-H4 Ig, which also modulates T cells function via decreasing inflammatory T-cell responses while increasing Treg function. In the case of tumor and tumor-associated macrophage expressed B7-H4, the interaction of the B7-H4R-expressing T cells with B7-H4-expressing tumor cells or tumor-associated macrophages would decrease the inflammatory and proliferative response by the T cells, while increasing the number and function of the Treg cells. Therefore, the blockade of the B7-H4: B7-H4R interaction is hypothesized to allow for the maintenance of the inflammatory T-cell response within the tumor microenvironment
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