Cell · 2024
Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.
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Yu Jiali, Yan Yijian, Li Shasha, Xu Ying, Parolia Abhijit, Rizvi Syed, Wang Weichao, Zhai Yiwen, Xiao Rongxin, Li Xiong, Liao Peng, Zhou Jiajia, Okla Karolina, Lin Heng, Lin Xun, Grove Sara, Wei Shuang, Vatan Linda, Hu Jiantao, Szumilo Justyna, Kotarski Jan, Freeman Zachary T, Skala Stephanie, Wicha Max, Cho Kathleen R, Chinnaiyan Arul M, Schon Samantha, Wen Fei, Kryczek Ilona, Wang Shaomeng, Chen Lieping, Zou Weiping
Аннотация
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.