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: 10210557
• 负责人: EDGAR G. ENGLEMAN
• 金额: $ 53.17万
• 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/10210557
• 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。 在远处组织中长出之前的结节(LN)。而转移到淋巴结通常归因于被动转移。 肿瘤淋巴管引流、LN转移机制及其在肿瘤中的作用 进展情况仍然知之甚少。LNS是适应性免疫反应的教育中心和港湾 大多数潜在的肿瘤反应性淋巴细胞。最近，我们发现在淋巴结的定植中，肿瘤 细胞通过与白细胞相互作用诱导肿瘤特异性免疫耐受，随后 在宿主中循环，导致全身耐受，促进远处转移性播种。 假设和目的：我们假设通过靶向诱导LNS的免疫耐受， 我们既可以防止远处转移，又可以诱导肿瘤消退。我们将使用多项尖端技术 方法鉴定LN耐受诱导的细胞和分子机制及发展途径 为打破它而道歉。这些目标将以下列目标为目标： 具体目标：目标1：确定淋巴转移诱导肿瘤特异性的机制 免疫耐受是通过激活免疫抑制淋巴细胞群来实现的。目标2：确定 表观遗传调控在LN转移和耐受诱导中的作用。目标3：调查 针对LNS肿瘤免疫耐受的免疫治疗方法。 研究设计和方法：采用高含量多重显微镜、质量细胞术、光转化- 基于谱系追踪、TCR测序和抗原呈递的小鼠遗传模型，我们将剖析 我们假设的LNS中的细胞相互作用负责耐受的诱导和传播，以及 在人体组织和数据集中验证这一发现。转移性肿瘤细胞具有保守性和稳定性 转录图谱表明表观遗传重新编程。我们将评估表观遗传改变的作用 在使用亚硫酸氢盐测序和ATAC-SEQ赋予PRO-LN转移转录特征时，以及 使用T-ATAC-seq来阐明耐受T细胞内识别 肿瘤抗原。我们将评估我们的新型免疫刺激抗体结合物的能力，有针对性的 具体到淋巴结，为了重新编程转移性淋巴结中的APC，使用HDAC抑制剂来重新编程这两种恶性肿瘤 和远离肿瘤免疫耐受的淋巴细胞群体，并结合这些策略来诱导稳健 黑色素瘤和pDAC小鼠模型的抗肿瘤联合治疗。 预期成果和影响：在这项工作成功结束后，我们将确定 淋巴转移诱导全身耐受的机制及新型免疫治疗的评价 克服这些机制的战略。