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

项目总结/摘要 前列腺癌（PCa）是最常诊断的癌症和第二大癌症原因 美国男性的死亡。雄激素剥夺疗法延长了患者的寿命，但可能导致疾病进展 去势抵抗性前列腺癌（CRPC）。此外，下一代抗雄激素治疗通常 导致对神经内分泌前列腺癌的进一步抗性和分化。最近，免疫疗法， 例如免疫检查点抑制剂已经成为非常感兴趣的领域。然而，CRPC显示， 对免疫检查点抑制剂的反应差，由于其免疫抑制性质。因此，我们需要更好的 了解在晚期PCa中常见的遗传改变如何塑造肿瘤免疫 微环境（TIME），以便为更好的靶向免疫方法的设计提供信息。我们 本研究旨在探讨上皮转录因子FOXA 1在调节细胞凋亡中的作用。 时间在PCa。FOXA 1在CRPC中被发现下调，并且是CRPC中最高度突变的基因之一。 PCa。与此相一致，我们先前已经表明FOXA 1缺失或突变诱导上皮间质细胞分化， 过渡和转移。然而，FOXA 1功能丧失是否诱导免疫抑制时间， 对PCa的了解仍然很少。在初步研究中，我们注意到炎症细胞因子，如 CCL 2、TGFB 3和IL 8，它们与免疫抑制性髓源性 抑制细胞和肿瘤相关巨噬细胞，是最高度上调的基因之一， FOXA 1缺失或突变。在我们研究FOXA 1抑制表达的机制中， 我们鉴定了ARID 1A作为FOXA 1共阻遏物。值得注意的是，我们发现FOXA 1和 ARID 1A蛋白相互作用并在PCa细胞的染色质上表现出广泛的共占据。此外，委员会认为， ARID 1A抑制基因也富含炎症途径。因此，我们假设FOXA 1 PCa的缺失或突变释放ARID 1A并诱导表观遗传重编程和炎症反应。 细胞因子信号传导，从而促进免疫抑制性肿瘤微环境和PCa 进展我们在这里提出：（1）破译野生型和突变型的分子机制， FOXA 1调节炎性细胞因子信号传导，和（2）确定FOXA 1丢失或突变的程度 在PCa中诱导免疫抑制性肿瘤微环境。

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.