Targeting Lymph Node Dependent Immune Tolerance in Cancer

针对癌症中的淋巴结依赖性免疫耐受

• 批准号: 10366092
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 52.36万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366092
• 关键词: Adoptive Transfer; Antigen Presentation; Antigen-Presenting Cells; Atypical lymphocyte; Binding Sites; Biological Assay; Cell Line; Cells; Cellular Assay; Cessation of life; Chromatin; Combined Modality Therapy; Cytometry; Data Set; Distant; Distant Metastasis; Drainage procedure; Education; Epigenetic Process; Exhibits; Gene Expression Profile; Genes; Genetic; Goals; Histone Deacetylase; Histone Deacetylase Inhibitor; Human; Immune; Immune Evasion; Immune Tolerance; Immune system; Immunosuppression; Immunotherapeutic agent; Leukocytes; Liver; Lung; Lymphatic; Lymphocyte; Malignant - descriptor; Malignant Neoplasms; Metastatic Neoplasm to Lymph Nodes; Methods; Microscopy; Modeling; Molecular; Neoplasm Metastasis; Organ; Organism; Pancreatic Ductal Adenocarcinoma; Population; Process; Research Design; Research Personnel; Resolution; Role; Site; System; T cell receptor repertoire sequencing; T-Cell Antigen Receptor Specificity; T-Lymphocyte; Therapeutic; Tissues; Transposase; Tumor Antigens; Work; adaptive immune response; analytical tool; antibody conjugate; base; bisulfite sequencing; cancer cell; epigenetic regulation; human tissue; lymph nodes; malignant lymphocyte; melanoma; mouse model; multidimensional data; neoplastic cell; new technology; novel; novel therapeutics; prevent; programs; transcription factor; tumor; tumor heterogeneity; tumor progression

Project Summary Background: Malignant melanoma and pancreatic ductal adenocarcinoma (PDAC) typically spread to lymph nodes (LNs) prior to outgrowth in distant tissues. While metastasis to LNs is frequently attributed to passive drainage from tumor lymphatics, the mechanisms enabling LN metastasis and its functional role in tumor progression remain poorly understood. LNs are education hubs of the adaptive immune response and harbor the majority of potentially tumor-reactive lymphocytes. Recently, we discovered that in colonizing LNs, tumor cells induce tumor-specific immune tolerance through their interactions with leukocytes that subsequently circulate throughout the host, resulting in systemic tolerance that facilitates metastatic seeding of distant sites. Hypothesis and objective: We hypothesize that by targeting the induction of immune tolerance in LNs, we can both prevent distant metastasis and induce tumor regression. We will use multiple cutting-edge methods to identify the cellular and molecular mechanisms of LN tolerance induction and develop approaches for breaking it. These goals will be pursued in the following aims: Specific Aims: Aim 1: Identify the mechanisms by which lymph node metastases induce tumor-specific immune tolerance through their activation of immunosuppressive lymphocyte populations. Aim 2: Determine the role of epigenetic regulation in LN metastasis and tolerance induction. Aim 3: Investigate immunotherapeutic approaches targeting tumor immune tolerance in LNs. Study design and methods: Using high-content multiplexed microscopy, mass cytometry, photoconversion- based lineage tracing, TCR sequencing, and genetic mouse models of antigen presentation, we will dissect the cellular interactions in LNs that we hypothesize are responsible for tolerance induction and dissemination, and validate the findings in human tissues and datasets. LN metastatic tumor cells exhibit conserved and stable transcriptional profiles indicative of epigenetic reprogramming. We will assess the role of epigenetic alterations in conferring a pro-LN metastatic transcriptional signature using bisulfite sequencing and ATAC-seq, and employ T-ATAC-seq to elucidate changes in the epigenetic landscape within tolerized T cells that recognize tumor antigens. We will evaluate the ability of our novel immunostimulatory antibody conjugates, targeted specifically to LNs, to reprogram APCs in metastatic LNs, employ HDAC inhibitors to reprogram both malignant and lymphocyte populations away from tumor immune tolerance, and combine these strategies to elicit robust anti-tumor combination therapies in mouse models of melanoma and PDAC. Expected results and impact: Upon successful conclusion of this work, we will have identified the mechanisms by which LN metastasis induces systemic tolerance, and evaluated novel immunotherapeutic strategies to overcome these mechanisms.

项目摘要 背景：恶性黑色素瘤和胰腺导管腺癌（PDAC）通常扩散到淋巴 在遥远组织中出现之前的节点（LNS）。虽然转移到LNS经常归因于被动 肿瘤淋巴管的排水，使LN转移的机制及其在肿瘤中的功能作用 进展仍然很少理解。 LNS是适应性免疫反应和港口的教育枢纽 大多数潜在的肿瘤反应性淋巴细胞。最近，我们发现在殖民LNS中，肿瘤 细胞通过与白细胞的相互作用诱导肿瘤特异性免疫耐受性 在整个宿主中循环，导致全身耐受性，促进遥远位点的转移播种。 假设和客观：我们通过靶向LNS中的免疫耐受性来假设 我们可以预防远处转移并诱导肿瘤消退。我们将使用多个前沿 鉴定LN耐受性诱导的细胞和分子机制的方法并开发方法 打破它。这些目标将在以下目的中实现： 特定目的：目标1：确定淋巴结转移诱导肿瘤特异性的机制 免疫耐受性通过其激活免疫抑制淋巴细胞种群。目标2：确定 表观遗传调节在LN转移和耐受诱导中的作用。目标3：调查 免疫治疗方法靶向LNS中肿瘤免疫耐受性。 研究设计和方法：使用高素质多重显微镜，质量细胞术，光转化 - 基于抗原表现的基于谱系跟踪，TCR测序和遗传小鼠模型，我们将剖析 我们假设的LN中的细胞相互作用负责耐受性诱导和传播，并且 验证人体组织和数据集中的发现。 LN转移性肿瘤细胞表现出保守和稳定 转录曲线指示表观遗传重编程。我们将评估表观遗传改变的作用 在使用Bisulfite测序和ATAC-SEQ和ATAC-SEQ和 采用T-ATAC-SEQ来阐明识别的T细胞内表观遗传景观的变化 肿瘤抗原。我们将评估我们的新型免疫刺激性抗体结合物的能力，靶向 专门针对LNS，重新编程转移性LNS中的APC，采用HDAC抑制剂重新编程两个恶性肿瘤 和淋巴细胞群体远离肿瘤免疫耐受性，并结合这些策略以引起强大的 黑色素瘤和PDAC小鼠模型中的抗肿瘤组合疗法。 预期结果和影响：这项工作成功结束后，我们将确定 LN转移诱导全身耐受性并评估新型免疫治疗性的机制 克服这些机制的策略。