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.