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

项目摘要/摘要 前列腺癌是最常见的癌症，也是第二大致癌原因。 美国男性死亡。雄激素剥夺疗法延长了患者的寿命，但可能会导致病情恶化 抗去势前列腺癌(CRPC)。此外，使用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耐药和分化。最近，免疫疗法， 例如免疫检查点抑制剂，已经成为一个令人感兴趣的领域。然而，CRPC已经表现出了 由于免疫抑制的性质，对免疫检查点抑制剂的反应较差。因此，我们需要一个更好的 了解进展期前列腺癌中常见的基因改变如何影响肿瘤免疫 微环境(时间)，以便为设计更有针对性的免疫治疗方法提供信息。我们 本研究拟探讨上皮转录因子Forkhead Box A1(FOXA1)在调节细胞周期中的作用。 在PCA中的时间。FOXA1在CRPC中被发现下调，是 PCA。因此，我们先前已经证明FOXA1缺失或突变诱导上皮-间充质形成 转移和转移。然而，FOXA1功能丧失是否会导致免疫抑制时间 对于PCA，人们仍然知之甚少。在初步研究中，我们注意到炎性细胞因子，如 CCL2、TGFB3和IL8与免疫抑制髓系来源的募集相关 抑制细胞和肿瘤相关巨噬细胞是最高上调的基因之一。 FOXA1缺失或突变。在我们对FOXA1抑制表达的机制的研究中 在炎性细胞因子中，我们确定ARID1A是FOXA1共抑制因子。值得注意的是，我们发现了FOXA1和 在PCa细胞中，ARID1A蛋白相互作用，并在染色质上表现出广泛的共占性。此外， ARID1A抑制基因也为炎症途径提供了丰富的信息。因此，我们假设FOXA1 PCa缺失或突变释放ARID1A，并诱导表观遗传重新编程和炎症 细胞因子信号转导，从而促进免疫抑制的肿瘤微环境和PCA 进步。我们在这里建议：(1)破译野生型和突变型 FOXA1调节炎症细胞因子信号，以及(2)决定FOXA1丢失或突变的程度 在前列腺癌中诱导免疫抑制的肿瘤微环境。

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.