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.

项目概要/摘要： 自1973年以来，皮肤黑色素瘤的发病率翻了一番，并且比任何其他疾病都增长得更快。 其他癌症。FDA批准的靶向抑制剂和免疫检查点疗法在以下人群中具有高应答率： 黑色素瘤;然而，先天性和获得性抗性仍然是重要的问题。联合收割机 靶向和免疫治疗显示出希望;然而，对串扰的全面理解 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 to novel新therapeutic治疗strategies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 研究未充分研究的免疫检查点蛋白VISTA的新调节。VISTA是一种抑制剂， 免疫检查点主要在造血细胞上表达。在一项新的发现中，我们观察到VISTA是 在患者样品和细胞系中的黑素瘤细胞上表达。它的肿瘤特异性表达促进了 体内肿瘤起始，与Foxp 3 + CD 4+调节性T细胞（T细胞）的增加相关。我们 证实BRAF抑制剂（BRAFi）处理减少VISTA表达，并且BRAFi诱导的VISTA表达降低。 F0 XD 3的上调负调节VISTA转录物水平。BRAF/MEK抑制剂在临床上使用， 这促使我们进一步研究VISTA的作用，VISTA是一种BRAF-FOXD 3调节的免疫检查点， 蛋白质，调节免疫反应。在第一个目标中，我们将测试肿瘤表达的假设， VISTA促进Treg诱导并增强Treg抑制功能。他汀类药物可限制 因此，我们还将测试VISTA的肿瘤特异性表达改变肿瘤免疫治疗的假设。 对PD-1阻断的反应。在K 00阶段，我们将广泛研究癌细胞信号通路， 使细胞在转移过程中逃避免疫检测。肿瘤细胞利用各种机制分离 转移到新的器官我们假设肿瘤内在信号通路 在转移期间的免疫逃避中起关键作用。在目标2中，我们将使用CRISPR/Cas9筛选， 自发转移模型以鉴定促进转移的基因。我们将比较 确定特异性促进转移的基因的免疫活性和免疫受损模型 在免疫系统的压力下。这些研究的完成将使我们对 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奠定了坚实的基础，为长期 目标是作为学术首席研究员开展肿瘤免疫学研究。