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.

B7-H1; Cell death; PI3Kγ; Targeted therapy.