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.

概括前列腺癌（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。雄激素剥夺疗法和雄激素受体（AR）途径抑制剂延伸患者的寿命（但耐药）经常发展，导致耐cast割前列腺癌（CRPC）。免疫疗法，例如免疫切除剂抑制剂（ICI），在某些取消中表现出了很大的希望。但是，CRPC对ICI的反应较差，主要是由于免疫抑制作用肿瘤浸润细胞，例如髓样衍生的抑制细胞（MDSC）和肿瘤相关的巨噬细胞（TAM）。这些细胞的积累抑制CD4+/CD8+ T细胞的生长和活性，导致免疫抑制作用肿瘤免疫微环境（时间）。 MDSC和TAM被炎性细胞因子吸引在肿瘤内部因素的调节下由肿瘤细胞分泌。 FOXA1是转录因素正常前列腺发育和分化是必需的。但是，FOXA1在CRPC中被下调，在大约12-13％的转移性CRPC中发现了FOXA1的体细胞突变。我们以前有表明FOXA1损失或突变会增加上皮到间质转变（EMT），谱系可塑性，细胞运动性和PCA转移，通过诱导炎症细胞因子（例如TGFB3和IL8）。但是，如何 FOXA1充当转录复制品，FOXA1是否调节PCA的免疫景观仍然未知。在初步研究中，我们发现FOXA1抑制了一系列炎性细胞因子，例如如TNFį，CCL2，CCL20，CXCL5，TGFB3和IL8，众所周知，它们招募了MDSC和TAM。从机械上讲，我们观察到FOXA1蛋白与SWI/SNF染色质亚基ARID1A相互作用重塑复合物已被证明充当转录复制品并抑制炎症卵巢癌的细胞因子。至关重要的是，具有前列腺特异性共同缺失的转基因小鼠模型的分析与PTEN小鼠相比，FOXA1和PTEN显示出更具侵略性的肿瘤，具有巨大的巨噬细胞浸润。因此，我们假设1）FOXA1将ARID1A蛋白募集到染色质进行表观遗传重塑和转录表示，2）FOXA1损失或突变释放ARID1A，导致炎症细胞因子诱导，免疫抑制时间和PCA进展。为了检验这些假设，在AIM 1中，我们将研究PCA中的FOXA1和ARID1A蛋白相互作用，染色质的同时占领和相互的相互作用炎症细胞因子转录表示的依赖性。我们还将确定如何与PCA相关的FOXA1突变破坏了功能。 AIM 2将调查FOXA1的部署转基因小鼠会影响PCA进展，ARIDA1A功能，细胞因子诱导和肿瘤免疫浸润并进一步验证人CRPC组织中的途径。