B7-H3 / CD276, identified in 2001, is a type I transmembrane protein that shares 20%–27% amino acid identity with other B7 family members.
Initial work on the functional properties of B7-H3 / CD276 showed a stimulatory effect of human B7-H3 / CD276 on T-cells. In vitro, B7-H3 immune checkpoint pathway was able to increase proliferation of both CD4+ and CD8+ T-cells, enhance the induction of cytotoxic T lymphocytes (CTLs), and selectively stimulate interferon-gamma (IFN-γ) production in the presence of anti-CD3 Abs to mimic the TCR signal . B7-H3 / CD276-driven antitumor immunity was mediated by CD8+ T-cells and NK cells. In an orthotopic murine colon cancer model, treatment by intratumoral injection of an adenovirus expressing mouse B7-H3 / CD276 (Ad-B7-H3-GFP) resulted in a reduction of tumor size compared to control animals.
In contrast to these findings,which strongly suggest a stimulatory effect of B7-H3 immune checkpoint pathway on T-cell responses and antitumor immunity, other groups have proposed opposite functions for B7-H3 / CD276. In mice, B7-H3 / CD276 protein inhibited T-cell activation and effector cytokine production. Furthermore, an antagonistic mAb to B7-H3 / CD276 enhanced T-cell proliferation in vitro and led to exacerbated experimental autoimmune encephalomyelitis (EAE) in vivo. Moreover, B7-H3 / CD276–/– mice developed more severe airway inflammation under conditions in which T helper cells differentiated toward Th1 rather than Th2. In a different in vitro study, B7-H3 immune checkpoint pathway inhibited T-cell proliferation of both CD4+ and CD8+ T-cells mediated by Ab to T-cell receptor or allogeneic APCs .
Martin Loos et al. B7-H3 and Its Role in Antitumor Immunity. Clinical and Developmental Immunology. 2010.
|Co-inhibitory immune checkpoint pathways||Co-stimulatory immune checkpoint pathways|
|PD1 & PD-L1 immune checkpoint pathway||CD40 & CD40L immune checkpoint pathway|
|CTLA-4 & CD80 (CD86) immune checkpoint pathway||OX40 & OX40L immune checkpoint pathway|
|B7-H4 / B7S1 / B7x immune checkpoint pathway||HVEM & LIGHT immune checkpoint pathway|
|HVEM & BTLA immune checkpoint pathway||CD28 & CD80 (CD86) immune checkpoint pathway|
|HVEM & CD160 immune checkpoint pathway||GITR & GITR Ligand immune checkpoint pathway|
|LAG3 / CD223 / Lymphocyte activation gene 3 immune checkpoint pathway||CD27 & CD70 immune checkpoint pathway|
|Galectin-9 & TIM-3 immune checkpoint pathway||4-1BB & 4-1BBL immune checkpoint pathway|
|Indoleamine 2,3-dioxygenase/IDO immune checkpoint pathway||ICOS & ICOS Ligand immune checkpoint pathway|
|VISTA / B7-H5 / GI24 immune checkpoint pathway||CD266 & CD155 immune checkpoint pathway|
|CEACAM1 / CD66a immune checkpoint pathway|
|SIRP alpha & CD47 immune checkpoint pathway|
|2B4 & CD48 immune checkpoint pathway|
|TIGIT & CD155 immune checkpoint pathway|