Welcome to the (B7) Family

The action of T cells in adaptive immunity is modulated by two important signaling pathways. The first pathway involves recognition of the major histocompatibility complex on the surface of antigen presenting cells. The second pathway is antigen-independent, but still essential for effective T cell response. It includes co-stimulation by members of the B7 family.

The B7 family has ten members and is divided into three phylogenetically distinct groups.¹ Groups I and II are involved in central and peripheral immune tolerance, respectively. Group III consists of more recently described immune checkpoint molecules.² One member of group III, B7 homolog 3 protein (B7-H3; also known as CD276), is a transmembrane protein first described in 2001 in humans,³ and later described in mice.⁴ B7-H3 is universally expressed among species and is one of the most evolutionarily conserved members of the B7 family.⁵ B7-H3 mRNA is widely expressed, while its protein expression is limited in normal tissue, suggestive of posttranscriptional regulation.^1,2 A soluble form of B7-H3 is also found in human sera, produced through alternate splicing of the intron or cleavage from the cell surface.⁶

The precise function(s) and role(s) of B7-H3 in T cell-mediated immunity remain controversial. Most studies report a co-inhibitory effect on T cell activation, but a costimulatory role has also been reported.^3,7 B7-H3 receptor(s) have not yet been identified.^2,7 The lack of identified receptors and the use of varied models used to study T cell-mediated immunity may explain the contradicting reports of B7-H3's function.

In line with its role as an immune checkpoint molecule, B7-H3 also plays a part in tumorigenesis and is overexpressed in a number of human malignancies.^8-10 B7-H3 modulates migration and invasion of various cancer cell types,¹¹ augments resistance to apoptosis,⁷ and weakens tumor sensitivity to chemotherapeutic drugs.¹² Together, these effects promote tumor aggression and invasiveness. Up to 93% of tissue from human tumors display aberrant B7-H3 expression, and high B7-H3 expression has been associated with poor prognosis and clinical outcome in cancer patients.⁷

The preferential expression of B7-H3 in tumor cells makes it an attractive target for cancer immunotherapy. Multiple clinical trials using monoclonal antibodies against B7-H3 are currently underway.¹³ Additional approaches to target B7-H3 may include bispecific antibodies, small molecule inhibitors, or a combination of treatments.⁷ The role of B7-H3 in immunity is clearly complex, but a better understanding of its exact function may represent a potent new approach to cancer treatment.