{Reference Type}: Journal Article
{Title}: Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.
{Author}: Yu J;Yan Y;Li S;Xu Y;Parolia A;Rizvi S;Wang W;Zhai Y;Xiao R;Li X;Liao P;Zhou J;Okla K;Lin H;Lin X;Grove S;Wei S;Vatan L;Hu J;Szumilo J;Kotarski J;Freeman ZT;Skala S;Wicha M;Cho KR;Chinnaiyan AM;Schon S;Wen F;Kryczek I;Wang S;Chen L;Zou W;
{Journal}: Cell
{Volume}: 0
{Issue}: 0
{Year}: 2024 Jun 28
{Factor}: 66.85
{DOI}: 10.1016/j.cell.2024.06.012
{Abstract}: Immune tolerance mechanisms are shared in cancer and pregnancy. Through cross-analyzing single-cell RNA-sequencing data from multiple human cancer types and the maternal-fetal interface, we found B7-H4 (VTCN1) is an onco-fetal immune tolerance checkpoint. We showed that genetic deficiency of B7-H4 resulted in immune activation and fetal resorption in allogeneic pregnancy models. Analogously, B7-H4 contributed to MPA/DMBA-induced breast cancer progression, accompanied by CD8+ T cell exhaustion. Female hormone screening revealed that progesterone stimulated B7-H4 expression in placental and breast cancer cells. Mechanistically, progesterone receptor (PR) bound to a newly identified -58 kb enhancer, thereby mediating B7-H4 transcription via the PR-P300-BRD4 axis. PR antagonist or BRD4 degrader potentiated immunotherapy in a murine B7-H4+ breast cancer model. Thus, our work unravels a mechanistic and biological connection of a female sex hormone (progesterone) to onco-fetal immune tolerance via B7-H4 and suggests that the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer.