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FOXA1 regulates cytokine signaling and immune landscape in prostate cancer through ARID1A

FOXA1 通过 ARID1A 调节前列腺癌中的细胞因子信号传导和免疫景观

基本信息

批准号：
10681898
负责人：
Jindan Yu
金额：
$ 51.34万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10681898
关键词：
ARID1A gene Affect American Androgen Receptor Atlas of Cancer Mortality in the United States Binding C-terminal CCL2 gene CCL20 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene CXCL5 gene Cancer Etiology Cell Survival Cells Cessation of life Chromatin Chromatin Remodeling Factor Clinical Collaborations Cytokine Signaling Dependence Development Enhancers Epigenetic Process Epithelium Gene Expression Genes Human IL8 gene Immune Immune checkpoint inhibitor Immunotherapy Impairment Induced Mutation Infiltration Inflammatory Intrinsic factor Knock-out Longevity Macrophage Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mediating Mesenchymal Metastasis Induction Metastatic Prostate Cancer Modeling Mus Mutate Mutation Myeloid-derived suppressor cells Neoplasm Metastasis Operative Surgical Procedures Pathway interactions Patients Phenotype Play Point Mutation Proliferating Prostate Proteins Radiation Regulation Regulatory T-Lymphocyte Reporting Repression Resistance Resistance development Role Shapes Signal Transduction Somatic Mutation TGFB3 gene Testing Therapeutic Tissues Transcription Coactivator Transcription Repressor Transgenic Mice Tumor Immunity Tumor-associated macrophages Tumor-infiltrating immune cells advanced prostate cancer androgen deprivation therapy cancer diagnosis castration resistant prostate cancer cell growth cell motility chromatin remodeling cytokine epigenomics epithelial to mesenchymal transition gene repression immune cell infiltrate inhibitor insight knock-down male men mouse model mutant neoplastic cell novel therapeutic intervention prostate cancer cell prostate cancer metastasis prostate cancer progression receptor recruit response single-cell RNA sequencing transcription factor transcriptome tumor tumor-immune system interactions tumorigenesis

项目摘要

Summary Prostate cancer (PCa) is the most commonly diagnosed cancer and the second leading cause of cancer death in American males. Androgen deprivation therapies and androgen receptor (AR) pathway inhibitors extend patient lifespan, yet resistance often develops, leading to castration-resistant prostate cancer (CRPC). Immunotherapies, such as immune checkpoint inhibitors (ICI), have shown great promise in some cancers. However, CRPC has displayed a poor response to ICI, mainly due to tumor infiltration by immunosuppressive cells, such as myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM). The accumulation of these cells inhibits CD4+/CD8+ T cell growth and activity, leading to an immunosuppressive tumor-immune microenvironment (TIME). MDSCs and TAMs are attracted by inflammatory cytokines that are secreted by the tumor cells under the regulation of tumor-intrinsic factors. FOXA1 is a transcription factor that is required for normal prostate development and differentiation. However, FOXA1 is down-regulated in CRPC, and somatic point mutations of FOXA1 were found in about 12-13% of metastatic CRPC. We have previously shown that FOXA1 loss or mutations increase epithelial-to-mesenchymal transition (EMT), lineage plasticity, cell motility, and PCa metastasis by inducing inflammatory cytokines such as TGFB3 and IL8. However, how FOXA1 acts as a transcriptional repressor and whether FOXA1 regulates the immune landscape of PCa remain unknown. In preliminary studies, we found that FOXA1 inhibits a panel of inflammatory cytokines, such as TNFĮ, CCL2, CCL20, CXCL5, TGFB3, and IL8 that are known to recruit MDSCs and TAMs. Mechanistically, we observed that FOXA1 protein interacts with ARID1A, a subunit of the SWI/SNF chromatin remodeling complex that has been shown to act as a transcriptional repressor and inhibit inflammatory cytokines in ovarian cancer. Critically, analyses of a transgenic mouse model with prostate-specific co-deletion of Foxa1 and Pten showed a more aggressive tumor with massive macrophage infiltration than the Pten mice. We thus hypothesize that 1) FOXA1 recruits ARID1A protein to the chromatin for epigenetic remodeling and transcriptional repression, 2) FOXA1 loss or mutation unleashes ARID1A, leading to inflammatory cytokine induction, an immunosuppressive TIME, and PCa progression. To test these hypotheses, in Aim 1, we will investigate FOXA1 and ARID1A protein interaction in PCa, co-occupancy on the chromatin, and mutual dependency for transcriptional repression of inflammatory cytokines. We will also determine how these functions are disrupted by PCa-associated FOXA1 mutations. Aim 2 will investigate how Foxa1 depletion in the transgenic mice affects PCa progression, Arida1a function, cytokine induction, and tumor immune infiltration and further validate the pathway in human CRPC tissues.

总结前列腺癌（PCa）是最常见的癌症，也是癌症死亡的第二大原因在美国男性中。雄激素剥夺疗法和雄激素受体（AR）通路抑制剂延长了患者的寿命，但耐药性往往发展，导致去势抵抗性前列腺癌（CRPC）。免疫治疗，如免疫检查点抑制剂（ICI），在某些癌症中显示出巨大的前景。然而，CRPC对ICI的反应较差，主要是由于免疫抑制剂的肿瘤浸润。细胞，如骨髓源性抑制细胞（MDSC）和肿瘤相关巨噬细胞（TAM）。的这些细胞的积累抑制了CD 4 +/CD 8 + T细胞的生长和活性，导致免疫抑制性T细胞增殖。肿瘤免疫微环境（TIME）MDSC和TAM被炎性细胞因子吸引，由肿瘤细胞在肿瘤内在因子的调节下分泌。FOXA 1是一种转录因子，是正常前列腺发育和分化所必需的。然而，FOXA 1在CRPC中下调，在转移性CRPC中发现约12-13%的FOXA 1的体细胞点突变。我们先前已经显示FOXA 1缺失或突变增加上皮-间充质转化（EMT），谱系可塑性，细胞运动性和通过诱导炎性细胞因子如TGFB 3和IL 8的PCa转移。但如何 FOXA 1作为转录抑制因子，FOXA 1是否调节前列腺癌的免疫景观仍然未知。在初步研究中，我们发现FOXA 1抑制一组炎性细胞因子，如如TNF α、CCL 2、CCL 20、CXCL 5、TGFB 3和IL 8，其已知募集MDSC和TAM。从机制上讲，我们观察到FOXA 1蛋白与SWI/SNF染色质的亚基ARID 1A相互作用一种重塑复合物，已被证明可作为转录抑制因子并抑制炎症反应，卵巢癌中的细胞因子关键是，分析前列腺特异性共缺失的转基因小鼠模型 Foxa 1和Pten的小鼠显示出比Pten小鼠更具侵袭性的肿瘤，具有大量的巨噬细胞浸润。因此，我们假设1）FOXA 1招募ARID 1A蛋白到染色质进行表观遗传重塑，转录抑制，2）FOXA 1缺失或突变释放ARID 1A，导致炎性细胞因子诱导、免疫抑制时间和PCa进展。为了验证这些假设，在目标1中，我们将研究PCa中FOXA 1和ARID 1A蛋白的相互作用，染色质上的共占据，以及相互作用。依赖于炎症细胞因子的转录抑制。我们还将确定这些功能被PCa相关的FOXA 1突变破坏。目标2将研究Foxa 1缺失如何在转基因小鼠影响PCa进展、Arida 1a功能、细胞因子诱导和肿瘤免疫并进一步验证人CRPC组织中的途径。