Tumor Intrinsic Regulation of Immune Evasion Pathways in Melanoma

黑色素瘤免疫逃避途径的肿瘤内在调节

• 批准号: 10014597
• 负责人: Sheera Rosenbaum
• 金额: $ 4.55万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2021-05-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10014597
• 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; Image; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunodeficient Mouse; Immunotherapy; Incidence; Individual; International; Lead; Libraries; Luciferases; MEKs; Malignant Neoplasms; Melanoma Cell; Metastatic Melanoma; Modeling; Mus; Neoplasm Metastasis; Organ; PD-1 blockade; Pathway interactions; Patients; Phase; Phenotype; Play; 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; Transgenic Mice; Tumor Immunity; Tumor-infiltrating immune cells; Up-Regulation; Work; Writing; anti-PD1 therapy; anti-tumor immune response; cancer cell; cancer therapy; career; checkpoint therapy; clinical implementation; effective therapy; experimental study; immune checkpoint; immunoregulation; in vivo; inhibitor/antagonist; insight; melanoma; mutant; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; 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： 皮肤黑色素瘤的发病率自1973年以来增加了一倍，并且比任何人都更快 其他癌症。 FDA批准的靶向抑制剂和免疫检查点疗法的应答率很高 黑色素瘤；但是，先天和获得的抵抗仍然是重大问题。结合的策略 靶向和免疫疗法显示出希望；但是，对串扰的全面理解 缺乏癌细胞和免疫细胞之间。我们的中心假设是肿瘤固有信号传导 调节抗肿瘤免疫反应，并阐明驱动这些相互作用的途径 进行新颖的治疗策略。通过成功完成以下两个目标，我们将获得 洞悉调节抗肿瘤免疫力的肿瘤固有信号通路。在F99阶段，我们是 调查了研究不足的免疫检查点蛋白远景的新调节。远景是一种抑制 免疫检查点主要在造血细胞上表达。在一个新颖的发现中，我们观察到远景是 在患者样品和细胞系中的黑色素瘤细胞上表达。其肿瘤特异性表达促进了 体内肿瘤起始，与FOXP3+ CD4+ T调节细胞（Tregs）的增加有关。我们 证明BRAF抑制剂（BRAFI）治疗降低了远景的表达，Brafi诱导 FOXD3的上调负调节的Vista转录水平。 BRAF/MEK抑制剂在临床上使用， 这激发了我们进一步研究Vista的作用，BRAF-FOXD3调节的免疫检查站 蛋白质，调节免疫反应。在第一个目标中，我们将测试以下假设 Vista促进Treg诱导并增强Treg抑制功能。 Tregs可以限制 免疫疗法；因此，我们还将检验以下假设：远景的肿瘤特异性表达改变了 对PD-1封锁的响应。在K00阶段，我们将广泛研究癌细胞信号传导途径 允许细胞在转移过程中逃避免疫检测。肿瘤细胞采用各种机制出发 来自原发性肿瘤部位并定居新器官。我们假设肿瘤固有信号通路 在转移期间的免疫逃避中起关键作用。在AIM 2中，我们将在A中使用CRISPR/CAS9屏幕 自发转移模型鉴定促进转移的基因。我们将比较结果 免疫胜任和免疫损害模型，以确定特异性促进转移的基因 当免疫系统的压力下。这些研究的完成将带来宝贵的见解 肿瘤和免疫细胞之间的复杂相互作用。这两个阶段提供的培训将建立 癌症生物学，肿瘤免疫学和转移的坚实基础，有助于长期 作为学术首席研究员进行肿瘤免疫学研究的目标。