B7-H4 / B7S1 / B7x has been found to be expressed at the mRNA and protein levels in many types of human cancers and negatively correlate with poor prognosis. Expression of B7-H4 / B7S1 / B7x in human tumors is most likely due to aberrant regulation of post-transcription in tumors, since its cell surface protein expression is rare in normal human tissues, though abundant B7-H4 / B7S1 / B7x mRNA is detected. B7-H4 / B7S1 / B7x was preferentially expressed in nondividing tumor cells from human gliomas and medulloblastomas.
Increased B7-H4 / B7S1 / B7x expression in tumor cells correlated with decreased cell apoptosis and enhanced outgrowth of tumors in several models, including the severe combined immunodeficiency (SCID)/Beige xenograft outgrowth model. B7-H4 / B7S1 / B7x has also been shown to be extensively and variably N-glycosylated, which may serve as a "barrier" mechanism to evade immunosurveillance. As reported, the role of B7-H4 immune checkpoint pathway in tumor progression may be to transform precancerous cells and then protect them from immunosurveillance. In addition, one study has shown that overexpression of B7-H4 / B7S1 / B7x promoted tumorigenesis of ovarian cancer in immunodeficient mice by increased proliferation rate, cell adhesion, migration, and invasion, implying that B7-H4 immune checkpoint pathway might have a direct effect on tumorigenesis independent of immunity. In another study, overexpression of B7-H4 / B7S1 / B7x on normal cells resulted in malignant cellular transformation of epithelial cells, perhaps by protecting the pretransformed cells from apoptosis, as siRNA knockdown of B7-H4 on tumor cell lines in vitro led to increased apoptosis. However, the direct effect of B7-H4 / B7S1 / B7x on tumorigenesis has been only demonstrated in the above two studies, thus the exact mechanisms need further investigation.
In the tumor microenvironment, in addition to tumor cells, tumor-infiltrating macrophages, and endothelial cells of small blood vessels have also been found to constitutively express B7-H4 / B7S1 / B7x. B7-H4 / B7S1 / B7x was highly expressed in tumor-associated macrophages in the ascites of ovarian cancer patients and contributed to tumor progression. B7-H4 immune checkpoint pathway blockade by antisense oligonucleotides restored the function of macrophages to stimulate T cells and led to tumor regression in vivo.
Changjun He et al. The Inhibitory Role of B7-H4 in Antitumor Immunity: Association with Cancer Progression and Survival. Clinical and Developmental Immunology. 2011: 8.
|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-H3 / CD276 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|