Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance 2475

Abstract Description 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 the PR-P300-BRD4 axis is targetable for treating B7-H4+ cancer. Funding Sources Supported by the NIH/NCI R01 grants (CA217648, CA123088, CA099985, CA193136, and CA152470), and the NIH/NCI through the University of Michigan Rogel Cancer Center (CA46592) to W.Z., and by the UTC-Yale Endowment to L.C.. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)