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

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

doi:10.1016/j.cell.2024.06.012

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. Epub 2024 Jul 4.

Authors

Jiali Yu¹, Yijian Yan¹, Shasha Li¹, Ying Xu¹, Abhijit Parolia², Syed Rizvi³, Weichao Wang¹, Yiwen Zhai⁴, Rongxin Xiao¹, Xiong Li¹, Peng Liao¹, Jiajia Zhou¹, Karolina Okla⁵, Heng Lin¹, Xun Lin¹, Sara Grove¹, Shuang Wei¹, Linda Vatan¹, Jiantao Hu⁶, Justyna Szumilo⁷, Jan Kotarski⁸, Zachary T Freeman⁹, Stephanie Skala², Max Wicha⁶, Kathleen R Cho², Arul M Chinnaiyan¹⁰, Samantha Schon¹¹, Fei Wen³, Ilona Kryczek¹, Shaomeng Wang¹², Lieping Chen¹³, Weiping Zou¹⁴

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: wzou@umich.edu.

PMID: 38968937
PMCID: PMC11344674 (available on 2025-08-22)
DOI: 10.1016/j.cell.2024.06.012

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.

MeSH terms

Animals
Breast Neoplasms / genetics
Breast Neoplasms / immunology
Breast Neoplasms / metabolism
CD8-Positive T-Lymphocytes / immunology
CD8-Positive T-Lymphocytes / metabolism
Cell Line, Tumor
Female
Humans
Immune Tolerance*
Mice
Mice, Inbred C57BL
Placenta / immunology
Placenta / metabolism
Pregnancy
Progesterone* / metabolism
Progestins* / metabolism
Progestins* / pharmacology
Receptors, Progesterone / metabolism
Transcription Factors / metabolism
V-Set Domain-Containing T-Cell Activation Inhibitor 1* / metabolism

Substances

V-Set Domain-Containing T-Cell Activation Inhibitor 1
Progestins
VTCN1 protein, human
Progesterone
Receptors, Progesterone
Transcription Factors
Vtcn1 protein, mouse

Abstract

MeSH terms

Substances

Grants and funding