Immune Regulation of Disseminated Cancer Cell Dormancy

播散性癌细胞休眠的免疫调节

• 批准号: 10201082
• 负责人: Julio A. Aguirre-Ghiso
• 金额: $ 8.47万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201082
• 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：大多数癌症患者不是死于原发性肿瘤，而是死于转移性疾病。之前 在形成致命转移的过程中，播散性癌细胞（DCC）可能会休眠长达数十年，如图所示。 最小残留病（MRD）的临床，有效的治疗是不可用的。免疫疗法 取得了重大进展。然而，大多数研究集中在原发性肿瘤。知之甚少 对于转移性疾病，特别是对于MRD。本提案的总体目标是揭示 参与休眠DCC和免疫系统之间相互作用的机制，因此揭示了 在MRD发展成全面致命疾病之前，为MRD提供治疗机会。我们将确定 休眠的DCC和相关免疫细胞相对于向外生长的转移的特定表型 使用单细胞RNA测序、质谱仪（或CyTOF）和Nanostring技术。一个重要 将在整个研究中使用的临床前模型是MMTV-ErbB 2小鼠， 在次级器官中休眠的DCC。与广泛使用的涉及移植已建立的 肿瘤或疫苗接种，该模型将更好地模拟患者的真实生活情况，因为免疫系统 从癌细胞诞生之日起就伴随着癌细胞一起进化。在目标1中，我们将确定T细胞是否抑制 DCCs通过诱导休眠及其机制。我们将测试T细胞耗竭是否允许 MMTV-ErbB 2模型中休眠DCC的再活化，以及作为补充的原位模型。我们 还将测试免疫细胞因子是否在3D类器官培养物和体内诱导DCC休眠，并确定 这些细胞因子的细胞来源。在目标2中，我们将确定DCC是否使用休眠程序来诱导 通过调节免疫检查点的免疫抑制/逃避。具体来说，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，以确定休眠程序通常是否被DCC用于避免免疫应答， 所以坚持下去。我们还将测试免疫检查点抑制剂是否能使免疫反应对休眠的 DCCs。总之，这些方法将使我们能够了解免疫系统是否诱导DCC休眠， 休眠程序能够避免免疫应答的抑制，并且如果这些免疫应答的干预， 这些进程将消除休眠的DCC。因此，这项研究应该揭示治疗MRD的治疗机会 从而最小化导致大多数癌症患者死亡的疾病复发。