%0 Journal Article
%T Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.
%A Yu J
%A Yan Y
%A Li S
%A Xu Y
%A Parolia A
%A Rizvi S
%A Wang W
%A Zhai Y
%A Xiao R
%A Li X
%A Liao P
%A Zhou J
%A Okla K
%A Lin H
%A Lin X
%A Grove S
%A Wei S
%A Vatan L
%A Hu J
%A Szumilo J
%A Kotarski J
%A Freeman ZT
%A Skala S
%A Wicha M
%A Cho KR
%A Chinnaiyan AM
%A Schon S
%A Wen F
%A Kryczek I
%A Wang S
%A Chen L
%A Zou W
%J Cell
%V 0
%N 0
%D 2024 Jun 28
%M 38968937
%F 66.85
%R 10.1016/j.cell.2024.06.012
%X 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.