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

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Progestogen-driven B7-H4 contributes to onco-fetal immune tolerance
Cell ( IF 45.5 ) Pub Date : 2024-07-04 , 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

Affiliation

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.
Department of Chemical Engineering, University of Michigan School of Engineering, Ann Arbor, MI, USA.
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, MI, USA.
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.
Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland.
Department of Oncological Gynecology and Gynecology, Medical University of Lublin, Lublin, Poland.
Unit for Laboratory Animal Medicine, University of Michigan, Ann Arbor, MI, USA.
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.
Department of Obstetrics and Gynecology, University of Michigan Medical School, Ann Arbor, MI, USA.
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.
Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
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.

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 () 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.

中文翻译：

孕激素驱动的 B7-H4 有助于肿瘤胎儿免疫耐受

免疫耐受机制在癌症和妊娠中是共有的。通过交叉分析多种人类癌症类型和母胎界面的单细胞 RNA 测序数据，我们发现 B7-H4 () 是一个肿瘤-胎儿免疫耐受检查点。我们发现，B7-H4 的遗传缺陷会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 诱导的乳腺癌进展，并伴有 CD8 T 细胞耗竭。女性激素筛查显示，黄体酮可刺激胎盘癌细胞和乳腺癌细胞中 B7-H4 的表达。从机制上讲，孕酮受体 (PR) 与新鉴定的 -58 kb 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 降解剂在小鼠 B7-H4 乳腺癌模型中增强免疫治疗。因此，我们的工作揭示了女性性激素（黄体酮）通过 B7-H4 与肿瘤胎儿免疫耐受之间的机制和生物学联系，并表明 PR-P300-BRD4 轴可作为治疗 B7-H4 癌症的目标。

更新日期：2024-07-04

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