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

Publisher: Cell Press Country of Publication: United States NLM ID: 0413066 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1097-4172 (Electronic) Linking ISSN: 00928674 NLM ISO Abbreviation: Cell Subsets: MEDLINE

Publication: Cambridge, Ma : Cell Press
Original Publication: Cambridge, MIT Press.

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

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.
Competing Interests: Declaration of interests W.Z. has served as a scientific advisor or consultant for Cstone, NextCure, and Hanchorbio. S. Wang is a co-founder and paid consultant of Ascentage Pharma Group International and owns stock in Ascentage. L.C. has been a scientific founder, consultant, and/or board observer for NextCure, Normunity, Tayu, Zai Lab, Tpioneer, Vcanbio, OncoC4, and GenomiCare and has sponsored research funds from NextCure, Normunity, and DynamiCure. This research is conducted independently and has not received resources from and is unrelated to the scientific and commercial pursuits of these industrial entities, including NextCure.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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R01 CA261985 United States CA NCI NIH HHS; R01 CA193136 United States CA NCI NIH HHS; P30 CA046592 United States CA NCI NIH HHS; R01 CA152470 United States CA NCI NIH HHS; R01 CA248430 United States CA NCI NIH HHS; R01 CA123088 United States CA NCI NIH HHS; R01 CA099985 United States CA NCI NIH HHS

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

0 (V-Set Domain-Containing T-Cell Activation Inhibitor 1)
0 (Progestins)
0 (VTCN1 protein, human)
4G7DS2Q64Y (Progesterone)
0 (Receptors, Progesterone)
0 (Transcription Factors)
0 (Vtcn1 protein, mouse)

Date Created: 20240705 Date Completed: 20240823 Latest Revision: 20240827

20240828

PMC11344674

10.1016/j.cell.2024.06.012

38968937