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

Autor:	Yu J; 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., Yan Y; 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., Li S; 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., Xu Y; 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., Parolia A; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA., Rizvi S; Department of Chemical Engineering, University of Michigan School of Engineering, Ann Arbor, MI, USA., Wang W; 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., Zhai Y; Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA., Xiao R; 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., Li X; 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., Liao P; 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., Zhou J; 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., Okla K; 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., Lin H; 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., Lin X; 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., Grove S; 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., Wei S; 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., Vatan L; 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., Hu J; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA., Szumilo J; Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland., Kotarski J; Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland., Freeman ZT; Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA., Skala S; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA., Wicha M; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA., Cho KR; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA., Chinnaiyan AM; 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., Schon S; Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA., Wen F; Department of Chemical Engineering, University of Michigan School of Engineering, Ann Arbor, MI, USA., Kryczek I; 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., Wang S; 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., Chen L; Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA., Zou W; 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.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2024 Aug 22; Vol. 187 (17), pp. 4713-4732.e19. Date of Electronic Publication: 2024 Jul 04.
DOI:	10.1016/j.cell.2024.06.012
Abstrakt:	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.)
Databáze:	MEDLINE
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