BHLHE22 drives the immunosuppressive bone tumor microenvironment and associated bone metastasis in prostate cancer

作者：Chi Yin, Min Wang, Yingzhao Wang, Qijun Lin, Kai‐Yuan Lin, Hong Du, Chuandong Lang, Yuhu Dai, Xinsheng Peng · 发表于：Journal for ImmunoTherapy of Cancer · 年份：2023 · DOI：10.1136/jitc-2022-005532 · 被引用次数：29 · 研究领域：Cancer-related gene regulation、Epigenetics and DNA Methylation、Immune cells in cancer

Background The molecular characteristics of prostate cancer (PCa) cells and the immunosuppressive bone tumor microenvironment (TME) contribute to the limitations of immune checkpoint therapy (ICT). Identifying subgroups of patients with PCa for ICT remains a challenge. Herein, we report that basic helix-loop-helix family member e22 (BHLHE22) is upregulated in bone metastatic PCa and drives an immunosuppressive bone TME. Methods In this study, the function of BHLHE22 in PCa bone metastases was clarified. We performed immunohistochemical (IHC) staining of primary and bone metastatic PCa samples, and assessed the ability to promote bone metastasis in vivo and in vitro. Then, the role of BHLHE22 in bone TME was determined by immunofluorescence (IF), flow cytometry, and bioinformatic analyses. RNA sequencing, cytokine array, western blotting, IF, IHC, and flow cytometry were used to identify the key mediators. Subsequently, the role of BHLHE22 in gene regulation was confirmed using luciferase reporter, chromatin immunoprecipitation assay, DNA pulldown, co-immunoprecipitation, and animal experiments. Xenograft bone metastasis mouse models were used to assess whether the strategy of immunosuppressive neutrophils and monocytes neutralization by targeting protein arginine methyltransferase 5 (PRMT5)/colony stimulating factor 2 (CSF2) could improve the efficacy of ICT. Animals were randomly assigned to treatment or control groups. Moreover, we performed IHC and correlation analyses to ...