FOXA1 loss-of-function induces inflammatory cytokine signaling and immune suppression in prostate cancer

FOXA1 功能丧失在前列腺癌中诱导炎症细胞因子信号传导和免疫抑制

基本信息

批准号：
10723093
负责人：
Lourdes Brea
金额：
$ 4.29万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-09 至 2024-09-08
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10723093
关键词：
ARID Domain ATAC-seq Affect American Androgen Antagonists Androgen Receptor Area Cancer Etiology Cells Cessation of life ChIP-seq Chromatin Chromatin Remodeling Factor Cytokine Gene Cytokine Signaling DNA Binding Domain Data Down-Regulation Epigenetic Process Epithelium Exhibits Flow Cytometry Gene Expression Genes Genetically Engineered Mouse Human Immune Immune checkpoint inhibitor Immunocompetent Immunofluorescence Immunologic Immunosuppression Immunotherapeutic agent Immunotherapy Induced Mutation Infiltration Inflammation Inflammatory Interleukin-8 Investigation Knock-out Ligands Longevity Malignant neoplasm of ovary Malignant neoplasm of prostate Maps Mediating Mesenchymal Metastatic Prostate Cancer Molecular Mutate Mutation Myeloid-derived suppressor cells Nature Neoplasm Metastasis Neuroendocrine Prostate Cancer Neurosecretory Systems Operative Surgical Procedures Pathway interactions Patient Care Patients Point Mutation Primary Neoplasm Prostate Proteins Quantitative Reverse Transcriptase PCR Radiation Regulation Reporting Repression Resistance Role Sampling Shapes Signal Induction Signal Transduction Site Testing Tissues Transforming Growth Factor Beta 2 Tumor Promotion Tumor-associated macrophages advanced prostate cancer androgen deprivation therapy anti-tumor immune response cancer diagnosis castration resistant prostate cancer cell motility chemokine cytokine design forkhead protein gene repression genetic corepressor histone modification immune cell infiltrate improved inhibitor interest knock-down loss of function male mouse model mutant next generation overexpression programs prostate cancer cell prostate cancer progression recruit replication factor C response single-cell RNA sequencing transcription factor transcriptome sequencing transforming growth factor beta3 tumor tumor-immune system interactions

项目摘要

PROJECT SUMMARY/ABSTRACT Prostate cancer (PCa) is the most commonly diagnosed cancer and second leading cause of cancer death in American males. Androgen deprivation therapies extend patient lifespan, but can result in progression to castration resistant prostate cancer (CRPC). Moreover, treatment with next generation antiandrogens often results in further resistance and differentiation to neuroendocrine prostate cancer. Recently, immunotherapies, such as immune checkpoint inhibitors, have become an area of much interest. However, CRPC has shown a poor response to immune checkpoint inhibitors, due to its immunosuppressive nature. Thus, we need a better understanding of how genetic alterations commonly seen in advanced PCa shape the tumor immune microenvironment (TIME), in order to inform the design of better-targeted immunotherapeutic approaches. We here propose to investigate the role of epithelial transcription factor Forkhead Box A1 (FOXA1) in regulating the TIME in PCa. FOXA1 is found to be downregulated in CRPC, and is among the most highly mutated genes in PCa. In accordance, we have previously shown that FOXA1 loss or mutation induces epithelial-mesenchymal transition and metastasis. However, whether FOXA1 loss-of-function induces an immunosuppressive TIME in PCa remains poorly understood. In preliminary studies, we noticed that inflammatory cytokines, such as CCL2, TGFB3, and IL8, which are associated with recruitment of immunosuppressive myeloid derived suppressor cells and tumor-associated macrophages, were among the most highly upregulated genes upon FOXA1 depletion or mutation. In our investigation of the mechanism by which FOXA1 represses the expression of inflammatory cytokines, we identified ARID1A as a FOXA1 co-repressor. Notably, we found FOXA1 and ARID1A proteins interacted and exhibited extensive co-occupancy on the chromatin in PCa cells. Moreover, ARID1A repressed genes were also enriched for inflammatory pathways. Thus, we hypothesize that FOXA1 loss or mutation in PCa unleashes ARID1A and induces epigenetic reprogramming and inflammatory cytokine signaling, thereby promoting an immunosuppressive tumor microenvironment and PCa progression. We here propose to: (1) decipher the molecular mechanisms by which wild type and mutant FOXA1 regulate inflammatory cytokine signaling, and (2) determine the extent to which FOXA1 loss or mutation induces an immunosuppressive tumor microenvironment in PCa.

项目摘要/摘要前列腺癌（PCA）是最常见的癌症和癌症的第二大原因美国男性死亡。雄激素剥夺疗法延长了患者的寿命，但可能导致进展抑制前列腺癌（CRPC）。此外，接下来的抗雄激素治疗导致对神经内分泌前列腺癌的进一步耐药性和分化。最近，免疫疗法，例如免疫检查点抑制剂，已成为引起人们关注的领域。但是，CRPC显示了由于其免疫抑制性质，对免疫检查点抑制剂的反应不佳。因此，我们需要更好了解晚期PCA中常见的遗传改变是如何形成肿瘤免疫的微环境（时间），以告知靶向更好的免疫治疗方法的设计。我们这里建议调查上皮转录因子叉子盒A1（FOXA1）在调节该的作用时间在PCA。发现FOXA1在CRPC中被下调，并且是最高度突变的基因之一 PCA。根据一致，我们以前表明FOXA1损失或突变会诱导上皮 - 间质过渡和转移。但是，FOXA1功能失效是否诱导免疫抑制时间在PCA中，人们的理解仍然很差。在初步研究中，我们注意到炎性细胞因子，例如 CCL2，TGFB3和IL8与免疫抑制髓样的募集有关抑制细胞和与肿瘤相关的巨噬细胞是最高上调的基因之一 FOXA1消耗或突变。在我们研究FOXA1抑制表达的机制中在炎症性细胞因子上，我们将ARID1A鉴定为FOXA1共抑制剂。值得注意的是，我们找到了Foxa1和 ARID1A蛋白在PCA细胞中的染色质上相互作用并表现出广泛的共占占其素。而且， ARID1A抑制基因也被富含炎症途径。因此，我们假设FOXA1 PCA中的丢失或突变释放ARID1A并诱导表观遗传重编程和炎症细胞因子信号传导，从而促进免疫抑制肿瘤微环境和PCA 进展。我们在这里提出：（1）破译野生型和突变体的分子机制 FOXA1调节炎症细胞因子信号传导，（2）确定FOXA1损失或突变的程度在PCA中诱导免疫抑制肿瘤微环境。