Tumor Intrinsic Regulation of Immune Evasion Pathways in Breast Cancer

乳腺癌免疫逃避途径的肿瘤内在调节

• 批准号: 10613997
• 负责人: Sheera Rosenbaum
• 金额: $ 9.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-12 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10613997
• 关键词: Adopted; Adoptive Transfer; BRAF gene; Biopsy; CD4 Positive T Lymphocytes; CRISPR screen; Cancer Biology; Cell Line; Cells; Cessation of life; Clinical; Complex; Critical Pathways; Critical Thinking; Cutaneous Melanoma; Data; Detection; Disease; FDA approved; FOXP3 gene; Fellowship; Flow Cytometry; Foundations; Genes; Goals; Growth; Hematopoietic; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunodeficient Mouse; Immunotherapy; Incidence; Individual; Infiltration; International; Libraries; Luciferases; MEKs; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Mus; Neoplasm Metastasis; Organ; PD-1 blockade; Pathway interactions; Patients; Phase; Phenotype; Play; Postdoctoral Fellow; Primary Neoplasm; Principal Investigator; Proteins; Regulation; Regulatory T-Lymphocyte; Research; Research Project Grants; Resistance; Role; Sampling; Scientist; Signal Pathway; Signal Transduction; Site; Skin Cancer; Solid; T-Cell Proliferation; Techniques; Testing; Time; Training; Transcript; Transfection; Transgenic Mice; Tumor Immunity; Tumor Promotion; Up-Regulation; Work; Writing; anti-PD1 therapy; anti-tumor immune response; bioluminescence imaging; cancer cell; career; checkpoint therapy; clinical implementation; effective therapy; experimental study; immune checkpoint; immunoregulation; in vivo; inhibitor; insight; malignant breast neoplasm; melanoma; mutant; neoplastic cell; novel; novel therapeutic intervention; pre-clinical; pressure; response; skills; symposium; targeted treatment; transcription factor; tumor; tumor growth; tumor immunology; tumor initiation

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.

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，并且增长速度比任何癌症都快。 其他癌症。 FDA 批准的靶向抑制剂和免疫检查点疗法在以下领域具有较高的缓解率 黑色素瘤；然而，先天的和后天的抵抗力仍然是重大问题。结合的策略 靶向和免疫治疗显示出希望；然而，对串扰的全面了解 癌细胞和免疫细胞之间缺乏联系。我们的中心假设是肿瘤内在信号传导 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 新的治疗策略。通过成功完成以下两个目标，我们将获得 深入了解调节抗肿瘤免疫的肿瘤内在信号通路。在F99阶段，我们是 研究正在研究的免疫检查点蛋白 VISTA 的新调控。 VISTA 是一种抑制 免疫检查点主要表达于造血细胞。在一项新颖的发现中，我们观察到 VISTA 在患者样本和细胞系中的黑色素瘤细胞上表达。其肿瘤特异性表达被促进 体内肿瘤的发生与 Foxp3+ CD4+ T 调节细胞 (Treg) 的增加相关。我们 证明 BRAF 抑制剂 (BRAFi) 治疗可降低 VISTA 表达，并且 BRAFi 诱导的 FOXD3 的上调负向调节 VISTA 转录水平。临床上使用BRAF/MEK抑制剂， 这促使我们进一步研究 BRAF-FOXD3 调节的免疫检查点 VISTA 的作用 蛋白质，调节免疫反应。在第一个目标中，我们将检验肿瘤表达的假设 VISTA 促进 Treg 诱导并增强 Treg 抑制功能。 Tregs 可以限制功效 免疫疗法；因此，我们还将检验 VISTA 的肿瘤特异性表达改变了这一假设 对 PD-1 阻断的反应。在K00阶段，我们将广泛研究癌细胞信号通路 让细胞在转移过程中逃避免疫检测。肿瘤细胞利用多种机制来离开 从原发肿瘤部位转移并定植新器官。我们假设肿瘤内在信号通路 在转移过程中的免疫逃避中发挥关键作用。在目标 2 中，我们将在 自发转移模型来识别促进转移的基因。我们将比较结果 免疫活性和免疫受损模型以确定特异性促进转移的基因 当受到免疫系统的压力时。完成这些研究将为我们带来宝贵的见解 肿瘤和免疫细胞之间复杂的相互作用。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奠定了坚实的基础，为长期研究做出了贡献 作为学术首席研究员进行肿瘤免疫学研究的目标。