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Updated: Jun 21, 2025
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Isolation of Leukocytes from the Murine Tissues at the Maternal-Fetal Interface
Published on: May 21, 2015
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Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance
Jiali Yu1, Yijian Yan1, Shasha Li1
1Department of Surgery, University of Michigan Medical School, Ann Arbor, MI, USA; Center of Excellence for Cancer Immunology and Immunotherapy, University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
Cell
|July 5, 2024
Summary
B7-H4 acts as an onco-fetal immune checkpoint, crucial for both cancer progression and pregnancy. Targeting the progesterone-driven pathway offers a new strategy for treating B7-H4-positive cancers.
Area of Science:
- Immunology
- Reproductive Biology
- Oncology
Background:
- Immune tolerance mechanisms are critical in both cancer and pregnancy.
- B7-H4 (VTCN1) is identified as a key player in these shared processes.
Purpose of the Study:
- To investigate the role of B7-H4 in cancer and pregnancy immune tolerance.
- To elucidate the regulatory mechanisms of B7-H4 expression by female hormones.
- To explore therapeutic strategies targeting the B7-H4 pathway in cancer.
Main Methods:
- Cross-analysis of single-cell RNA-sequencing data from human cancers and the maternal-fetal interface.
- Utilizing allogeneic pregnancy models and MMTV/DMBA-induced breast cancer models.
- Progesterone receptor (PR) binding site analysis and investigation of the PR-P300-BRD4 axis.
- Assessing the efficacy of PR antagonists and BRD4 degraders in a murine cancer model.
Main Results:
- B7-H4 deficiency led to immune activation and fetal resorption in pregnancy models.
- B7-H4 promoted breast cancer progression and CD8+ T cell exhaustion.
- Progesterone directly stimulates B7-H4 expression in placental and cancer cells via the PR-P300-BRD4 axis.
- Therapeutic targeting of the PR-P300-BRD4 axis enhanced immunotherapy in a B7-H4+ breast cancer model.
Conclusions:
- B7-H4 serves as an onco-fetal immune checkpoint, linking progesterone to immune tolerance.
- The progesterone-PR-P300-BRD4 axis is a critical regulator of B7-H4 expression.
- Targeting this axis presents a promising therapeutic avenue for B7-H4-positive cancers, potentially improving immunotherapy outcomes.
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