Welcome to the (B7) Family

The adaptive immune system relies on T cells to recognize and respond to both native and foreign antigens. Appropriate T cell response is required for maintaining self-tolerance and eliminating pathogens, while aberrant T cell response can lead to autoimmune disease, rejection of transplanted organs, or cancer.

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.


1. Li G, Quan Y, Che F, Wang L. 2018. B7-H3 in tumors: friend or foe for tumor immunity? Cancer Chemother Pharmacol. Feb;81(2):245-253.

2. Janakiram M, Shah U, Liu W, Zhao A, Schoenberg M, Zang X. 2017. The third group of the B&-CD28 immune checkpoint family: HHLA2, TMIGD2, Bx& and B7-H3. Immunol Rev. Mar;276(1):26-39.

3. Chapoval A, Ni J, Lau J, Wilcox R, Flies D, Liu D, et al. 2001. B7-H3: a costimulatory molecule for T cell activation and IFN-gamma production. Nat Immunol. Mar;2(3):269-274.

4. Sun M, Richards S, Prasad DVR, Mai XM, Rudensky A, Dong C. 2002. Characterization of mouse and human B7-H3 genes. J Immunol. Jun 15;168(12):6294-6297.

5. Sun J, Fu F, Gu W, Yan R, Zhang G, Shen Z, et al. 2011. Origination of new immunological functions in the costimulatory molecule B7-H3: the role of exon duplication in evolution of the immune system. PLoS One. 2011;6(9):e24751.

6. Chen W, Liu P, Wang Y, Nie W, Li Z, Xu W, et al. 2013. Characterization of a soluble B7-H3 (sB7-H3) spliced from the intron and analysis of sB7-H3 in the sera of patients with hepatocellular carcinoma. PLoS One. Oct 23;8(10):e76965.

7. Picarda E, Ohaegbulam KC, Zang X. 2016. Molecular pathways: targeting B7-H3 (CD276) for human cancer immunotherapy. Clin Cancer Res. Jul 15;22(14):3425-3431.

8. Ingebrigtsen VA, Boye K, Nesland JM, Nesbakken A, Flatmark K, Fodstad O. 2014. B7-H3 expression in colorectal cancer: associations with clinicopathological parameters and patient outcome. BMC Cancer. Aug 20;14:602.

9. Hu Y, Lv X, Wu Y, Xu J, Wang L, Chen W, et al. 2015. Expression of costimulatory molecule B7-H3 and its prognostic implications in human acute leukemia. Hematology. May;20(4):187-195.

10. Sun J, Guo Y-D, Li X-N, Zhang Y-Q, Gu L, Wu P-P, et al. 2014. B7-H3 expression in breast cancer and upregulation of VEGF through gene silence. OncoTargets Ther. Oct;7:1979-1986.

11. Ingebrigtsen VA, Boye K, Tekle C, Nesland JM, Flatmark K, Fodstad O. 2012. B7-H3 expression in colorectal cancer: nuclear localization strongly predicts poor outcome in colon cancer. Int J Cancer. Dec;131(11):2528-2536.

12. Liu H, Tekle C, Chen Y-W, Kristian A, Zhao Y, Zhou M, et al. 2011. B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation. Mol Cancer Ther. Jun;10:960-971.

13. Clinicaltrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). Accessed 2018 Apr 11. Available from: https://clinicaltrials.gov/ct2/results?cond=b7-h3