Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance PMID: 38968937

ADC Targets in Oncology

2026-04-10

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

Cell. 2024 Aug 22;187(17):4713-4732.e19. doi: 10.1016/j.cell.2024.06.012.

Jiali Yu ¹ , Yijian Yan ¹ , Shasha Li ¹ , Ying Xu ¹ , Abhijit Parolia ² , Syed Rizvi ³ , Weichao Wang ¹ , Yiwen Zhai ⁴ , Rongxin Xiao ¹ , Xiong Li ¹ , Peng Liao ¹ , Jiajia Zhou ¹ , Karolina Okla ⁵ , Heng Lin ¹ , Xun Lin ¹ , Sara Grove ¹ , Shuang Wei ¹ , Linda Vatan ¹ , Jiantao Hu ⁶ , Justyna Szumilo ⁷ , Jan Kotarski ⁸ , Zachary T Freeman ⁹ , Stephanie Skala ² , Max Wicha ⁶ , Kathleen R Cho ² , Arul M Chinnaiyan ¹⁰ , Samantha Schon ¹¹ , Fei Wen ³ , Ilona Kryczek ¹ , Shaomeng Wang ¹² , Lieping Chen ¹³ , Weiping Zou ¹⁴

Affiliations

1. Department 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.
2. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA.
3. Department of Chemical Engineering, University of Michigan School of Engineering, Ann Arbor, MI, USA.
4. Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.
5. Department 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; Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland.
6. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
7. Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland.
8. Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland.
9. Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
10. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
11. Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA.
12. Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA; Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI, USA.
13. Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
14. Department 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; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI, USA; Graduate Program in Cancer Biology, University of Michigan, Ann Arbor, MI, USA. Electronic address: [email protected].

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⁺ 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.

Keywords

B7-H4; BRD4; T cell exhaustion; cancer; enhancer; immune checkpoint; immunotherapy; onco-fetal immune tolerance; pregnancy; progesterone.