美国密歇根大学医学院Weiping Zou团队近期取得重要工作进展，他们研究提出，孕激素驱动的B7-H4有助于胎儿免疫耐受。相关研究成果2024年7月4日在线发表于《细胞》杂志上。

据介绍，免疫耐受机制在癌症和妊娠中是共同的。

通过交叉分析来自多种人类癌症类型和母婴界面的单细胞RNA序列数据，研究人员发现B7-H4（VTCN1）是一个胎儿免疫耐受检查点。B7-H4基因缺陷导致同种异体妊娠模型中的免疫激活和胎儿吸收。类似地，B7-H4促进MPA/DMBA诱导的乳腺癌症进展，同时伴有CD8⁺ T细胞耗竭。

女性激素筛查显示，孕酮刺激胎盘和乳腺癌症细胞中B7-H4的表达。从机制上讲，孕激素受体（PR）与新鉴定的一个58kb增强子结合，从而通过PR-P300-BRD4轴介导B7-H4转录。PR拮抗剂或BRD4降解剂增强小鼠B7-H4⁺乳腺癌症模型中的免疫疗法。

总之，这一工作揭示了女性性激素(孕酮)通过B7-H4与胎儿免疫耐受的机制和生物学联系，并表明PR-P300-BRD4轴是治疗B7-H4⁺癌症的靶标。

附：英文原文

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

Author: 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

Issue&Volume: 2024-07-04

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.

DOI: 10.1016/j.cell.2024.06.012

Source: https://www.cell.com/cell/fulltext/S0092-8674(24)00652-4