Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 38968937.
- Also identified by DOI 10.1016/j.cell.2024.06.012 and PMC identifier 11344674.
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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<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> cancer.
Medical subject headings
- V-Set Domain-Containing T-Cell Activation Inhibitor 1
- Immune Tolerance
- Progestins
- Progesterone