Tumor Intrinsic Regulation of Immune Evasion Pathways in Breast Cancer

项目摘要/摘要： 自1973年以来，皮肤黑色素瘤的发病率翻了一番，而且增长速度比以往任何时候都快。 其他癌症。FDA批准的靶向抑制剂和免疫检查点疗法在 黑色素瘤；然而，先天的和后天的抵抗仍然是重要的问题。相结合的战略 靶向和免疫疗法显示出希望；然而，对相声的全面理解 缺乏癌细胞和免疫细胞之间的联系。我们的中心假设是肿瘤的内在信号 调节抗肿瘤免疫反应，阐明驱动这些相互作用的途径可以导致 到新的治疗策略。通过成功完成以下两个目标，我们将获得 洞察调节抗肿瘤免疫的肿瘤内在信号通路。在F99阶段，我们 研究未被研究的免疫检查点蛋白VistA的一种新的调节。Vista是一种抑制 免疫检查点主要表达在造血细胞上。在一个新的发现中，我们观察到Vista是 在患者样本和细胞系的黑色素瘤细胞上表达。其肿瘤特异性表达促进 肿瘤在体内启动，与Foxp3+CD4+T调节细胞(Tregs)的增加相关。我们 证明BRAF抑制剂(BRAFi)处理降低了Vista的表达，并诱导了 上调FOXD3负性调控的VistA转录水平。BRAF/MEK抑制剂用于临床， 这促使我们进一步研究Vista的作用，Vista是BRAF-FOXD3调节的免疫检查点 蛋白质，在调节免疫反应中。在第一个目标中，我们将检验这样一个假设，即肿瘤表达 Vista可促进Treg诱导并增强Treg抑制功能。Tregs可以限制药物的疗效 免疫疗法；因此，我们还将检验Vista的肿瘤特异性表达改变 对PD-1封锁的反应。在K00阶段，我们将广泛研究癌细胞信号通路 允许细胞在转移过程中逃避免疫检测。肿瘤细胞使用各种机制离开 从原发肿瘤部位转移到新器官。我们假设肿瘤的内在信号通路 在转移过程中的免疫逃逸中起着关键作用。在Aim 2中，我们将在 自发转移模型，以确定促进转移的基因。我们将比较以下结果： 用于确定特异性促进转移的基因的免疫活性和免疫受损模型 当受到免疫系统的压力时。这些研究的完成将为 肿瘤和免疫细胞之间复杂的相互作用。在这两个阶段提供的培训将建立 在癌症生物学、肿瘤免疫学和转移方面有坚实的基础，有助于长期 作为学术首席研究员开展肿瘤免疫学研究的目标。

Project Summary/Abstract: The incidence rate of cutaneous melanoma has doubled since 1973, and is increasing more rapidly than any other cancer. FDA-approved targeted inhibitors and immune checkpoint therapies have high response rates in melanoma; however, both innate and acquired resistance remain significant issues. Strategies that combine targeted and immune therapy show promise; however, a comprehensive understanding of the crosstalk between cancer cells and immune cells is lacking. Our central hypothesis is that tumor intrinsic signaling modulates the anti-tumor immune response, and elucidation of pathways that drive these interactions can lead to novel therapeutic strategies. Through the successful completion of the following two aims, we will gain insight into tumor intrinsic signaling pathways that regulate anti-tumor immunity. In the F99 phase, we are investigating a novel regulation of the understudied immune checkpoint protein VISTA. VISTA is an inhibitory immune checkpoint primarily expressed on hematopoietic cells. In a novel finding, we observed that VISTA is expressed on melanoma cells in patient samples and in cell lines. Its tumor-specific expression promoted tumor initiation in vivo, associated with an increase in Foxp3+ CD4+ T regulatory cells (Tregs). We demonstrated that BRAF inhibitor (BRAFi) treatment reduced VISTA expression, and BRAFi-induced upregulation of FOXD3 negatively regulated VISTA transcript levels. BRAF/MEK inhibitors are used clinically, which motivates us to further investigate the role of VISTA, a BRAF-FOXD3-regulated immune checkpoint protein, in modulating immune responses. In the first aim, we will test the hypothesis that tumor-expressed VISTA promotes Treg induction and enhances Treg suppressive function. Tregs can limit the efficacy of immunotherapy; thus, we will also test the hypothesis that tumor-specific expression of VISTA alters the response to PD-1 blockade. In the K00 phase, we will broadly investigate cancer cell signaling pathways that allow cells to evade immune detection during metastasis. Tumor cells employ various mechanisms to depart from the primary tumor site and colonize new organs. We hypothesize that tumor intrinsic signaling pathways play a critical role in immune evasion during metastasis. In aim 2, we will use a CRISPR/Cas9 screen in a spontaneous metastasis model to identify genes that promote metastasis. We will compare results between immune competent and immune compromised models to determine genes that specifically promote metastasis when under pressure from the immune system. Completion of these studies will bring valuable insights into the complex interactions between tumor and immune cells. The training provided in both of these phases will build a solid foundation in cancer biology, tumor immunology, and metastasis, contributing towards the long-term goal of conducting research on tumor immunology as an academic principal investigator.