Immune Regulation of Disseminated Cancer Cell Dormancy

播散性癌细胞休眠的免疫调节

• 批准号: 10513907
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 7.56万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513907
• 关键词: 3-Dimensional; Address; Anti-Inflammatory Agents; Appearance; Cancer Patient; Cells; Cessation of life; Clinic; Complement; Cues; Cytokine Receptors; Cytokine Signaling; Cytometry; Data; Development; Disease; ERBB2 gene; Equilibrium; Genes; Goals; Growth; Immune; Immune Evasion; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Tests; Immunosuppression; Immunotherapy; Interferons; Intervention; Lesion; Life; Ligands; Lung; Maps; Modeling; Mouse Mammary Tumor Virus; Mus; Neoplasm Metastasis; Organ; Organoids; PTPRC gene; Patients; Phase; Phenotype; Pre-Clinical Model; Primary Neoplasm; Process; Recurrence; Regulation; Relapse; Research; Residual Neoplasm; Secondary to; Seeds; Signal Transduction; Site; Source; T-Cell Depletion; T-Lymphocyte; Technology; Testing; Therapeutic; Transplantation; Vaccination; cancer cell; cytokine; effective therapy; immune checkpoint; immunoreaction; immunoregulation; in vivo; mouse model; nano-string; p38 Mitogen Activated Protein Kinase; preclinical evaluation; programs; single-cell RNA sequencing; transcription factor; tumor

SUMMARY: Most cancer patients do not die from primary tumors but from the metastatic disease. Before formation of lethal metastases, disseminated cancer cells (DCCs) may stay dormant for up to decades, shown in clinics as the minimal residual disease (MRD), for which effective therapies are unavailable. Immunotherapies have made significant progress. However, most of the research focuses on primary tumors. Much less is known for the metastatic disease, in particular for MRD. The overarching goal of this proposal is to uncover mechanisms involved in the interaction between dormant DCCs and the immune system and therefore reveal therapeutic opportunities for MRD before the development into a full-blown lethal disease. We will determine the specific phenotypes of dormant DCCs and the associated immune cells relative to outgrowing metastases using single-cell RNA-sequencing, mass cytometry (or CyTOF), and Nanostring technologies. An important preclinical model that will be used throughout the study is the MMTV-ErbB2 mice, which develop spontaneous dormant DCCs in secondary organs. Compared to widely used models involving transplantation of established tumors or vaccination, this model will better mimic real-life situations in patients, as the immune system co- evolve with the cancer cells since their inception. In Aim 1, we will determine if T cells inhibit the expansion of DCCs via induction of dormancy and the mechanisms involved. We will test if T cell depletion allows the reactivation of dormant DCCs in the MMTV-ErbB2 model but also an orthotopic model as a complement. We will also test if immune cytokines induce DCC dormancy in 3D organoid cultures and in vivo and determine the cellular source of these cytokines. In Aim 2, we will determine if DCCs use the dormancy program to induce immune-suppression/-evasion via regulation of immune checkpoints. Specifically, we will test if dormancy- inducing cytokines and transcription factors regulate expression of immunoregulatory factors. immune-evasion genes to determine if the dormancy program in general is used by DCCs to avoid immune response and therefore persist. We will also test if immune checkpoint inhibitors enable immune reactions against dormant DCCs. Together, these approaches will allow us to understand if the immune system induces DCC dormancy, if the dormancy program enables evasion of suppression of the immune response, and if intervention of these processes will eliminate dormant DCCs. Thus, this study should reveal therapeutic opportunities to treat MRD and thereby minimize the disease recurrence that kills the majority of cancer patients.

摘要：大多数癌症患者并非因原发性肿瘤而死，而是因转移性疾病而死亡。前 致命转移，传播癌细胞（DCC）的形成可能会处于休眠状态数十年，如图所示 诊所是最小残留疾病（MRD），为此无法获得有效疗法。免疫疗法 取得了重大进展。但是，大多数研究都集中在原发性肿瘤上。少得多 对于转移性疾病，尤其是MRD。该提议的总体目标是揭露 休眠DCC与免疫系统之间相互作用涉及的机制，因此揭示了 发展前MRD的治疗机会成熟致死疾病。我们将确定 休眠DCC的特定表型和相关的免疫细胞相对于生长的转移 使用单细胞RNA测序，质量细胞仪（或细胞）和纳米串技术。一个重要的 在整个研究中将使用的临床前模型是MMTV-ERBB2小鼠，它们会自发发展 二级器官的休眠DCC。与涉及已建立的移植的广泛使用的模型相比 肿瘤或疫苗接种，该模型将更好地模仿患者的现实情况，因为免疫系统共同 自癌细胞诞生以来随癌细胞的发展。在AIM 1中，我们将确定T细胞是否抑制 DCC通过诱导休眠和所涉及的机制。我们将测试T细胞耗尽是否允许 在MMTV-ERBB2模型中休眠DCC的重新激活，也是原位模型作为补体。我们 还将测试免疫细胞因子是否在3D器官培养物中诱导DCC休眠和体内并确定 这些细胞因子的细胞来源。在AIM 2中，我们将确定DCC是否使用休眠计划来诱导 通过调节免疫检查点的免疫抑制/抗态。具体而言，我们将测试休眠是否 诱导细胞因子和转录因子调节免疫调节因子的表达。免疫逃避 基因确定DCC是否通常使用休眠计划以避免免疫反应和 因此坚持不懈。我们还将测试免疫检查点抑制剂是否可以对休眠的免疫反应 DCCS。这些方法一起将使我们能够理解免疫系统是否引起DCC休眠，是否 休眠计划可以逃避对免疫反应的抑制，以及这些干预 过程将消除休眠的DCC。因此，这项研究应揭示治疗MRD的治疗机会 从而最大程度地减少杀死大多数癌症患者的疾病复发。