B7–H1 agonists suppress the PI3K/AKT/mtor pathway by degrading p110γ and independently induce cell death

The biological role of B7–H1 intrinsic signal is reportedly diverse and controversial, its signal pathway remains unclear. Although B7–H1 blocking antibodies were found to have agonist capacity, their binding features and agonist mechanisms need further investigation. Here, by constructing cell strains with full-length or truncated B7–H1, we found that B7–H1 functioned as a receptor to transmit cell death signal from PD-1 protein or anti-B7-H1s through its cytoplasmic domain. Specific binding to the IgV-like domain of B7–H1 was required for the downstream signal. Upon agonists interaction, B7–H1 regulated the degradation of phosphoinositide 3-kinases (PI3Ks) subunit p110γ, subsequently inhibited the PI3K/AKT/mTOR pathway, and significantly increased autophagy. Moreover, B7–H1 agonists also suppressed ubiquitylation in B7–H1+cells by reducing ubiquitin-activating enzyme (E1), eventually leading to cell death. Finally, we validated the receptor role of B7–H1 in multiple tumor cells and demonstrated that B7–H1 agonists could suppress tumor progression independent of T cells in vivo. Our findings revealed that B7–H1 agonists functions as a PI3K inhibitor and may offer new strategies for PI3K targeting therapy.