Cellular mechanisms by which exhausted T cell responses are restored

恢复疲惫的 T 细胞反应的细胞机制

• 批准号: 10585035
• 负责人: Thorsten Roman Mempel
• 金额: $ 48万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585035
• 关键词: Adhesives; Adopted; Antibodies; Antigen-Presenting Cells; Antigens; Blood; CXCR3 gene; CXCR6 gene; Cell Differentiation process; Cells; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cues; Cytotoxic T-Lymphocytes; Dendritic Cells; Disease; Distal; Endothelial Cells; Endothelium; Epigenetic Process; Equilibrium; Exposure to; Extravasation; Fibroblasts; Gatekeeping; Grant; Heart; Histology; Homeostasis; Hot Spot; Image Analysis; Immune; Immune system; Immunity; Immunologic Memory; Immunologics; Immunotherapeutic agent; Immunotherapy; Inflammation; Interleukin-12; Interleukin-15; Knowledge; Lead; Ligands; Lymphocyte Activation; Lymphocyte antigen; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mediating; Memory; Modeling; Mus; Myelogenous; Natural Killer Cells; Outcome; PD-1 blockade; Pathway interactions; Pericytes; Perivascular Neoplasm; Population; Population Dynamics; Positioning Attribute; Reporter; Reporting; Role; Signal Transduction; Site; T cell response; T cell transcription factor 1; T-Lymphocyte; T-Lymphocyte Subsets; TCF Transcription Factor; Testing; Tissues; Tumor Antigens; Tumor Tissue; Viral; Viral Cancer; Virus; Virus Diseases; Work; base; cancer cell; chemokine receptor; chronic infection; cytokine; cytotoxic; effector T cell; exhaust; exhaustion; functional adaptation; histological image; immune checkpoint; immune clearance; immunogenic; improved; in vivo; insight; intravital microscopy; loss of function; melanoma; migration; novel; pathogenic virus; prevent; programmed cell death protein 1; protein expression; quantitative imaging; receptor; recruit; response; restoration; self-renewal; spatial relationship; stem; stem-like cell; tumor; tumor growth; tumor microenvironment

Project Summary Exposure to pathogenic viruses that the immune system cannot rapidly clear leads to chronic viral infections. Cytotoxic T cell (CTL) responses against such viruses gradually adopt a epigenetically fixed, hypofunctional state commonly referred to as T cell exhaustion, which is thought to prevent immunopathological tissue damage from continuous high-level inflammation driven by antiviral CTL. A similar form of adaptation occurs in CTL responses against malignant tumors, and leads to increasing immunological tumor tolerance. In both chronic viral infection and malignancy, antibody blockade of so-called immune checkpoints, including the inhibitory PD-1 receptor expressed on activated CTL, can often restore exhausted CTL responses. However, the mechanisms by which this restoration occurs are incompletely understood. At the single cell level, CTL populations at effector sites of exhausted T cell responses consist of stem-like memory cells that express the transcription factor TCF-1 as well as TCF-1neg effector-like cells that transiently acquire full-fledged effector and cytokine-secreting function before eventually adopt a hypofunctional state of terminal differentiation. It recently emerged that PD-1 blockade does not restore the function of terminally differentiated cells, but acts primarily on TCF-1pos stem-like cells and causes them to divide, lose TCF-1 expression, and give rise to the highly proliferative transitory effector-like subset that mediates anti-viral or anti- tumor control. In prior work for this project we have characterized the critical role of the chemokine receptor CXCR6 to optimize the interaction of transitory effector-like CTL with a rare activated state of conventional dendritic cells called DC3, which trans-present IL-15 to CTL to promote their survival and accumulation in tumor tissue. DC3 densely cluster around micro-vessels in the tumor stroma to form perivascular niches, which we suggest may act as critical gatekeepers for CTL responses at sites of chronic inflammation. We propose to test the hypothesis that these perivascular niches are also sites for the maintenance of TCF-1pos stem-like CTL in tumor tissue, and for their conversion into effector-like cells. We will use highly multiplexed histological imaging of whole tumors and intravital microscopy to identify the chemotactic guidance cues by which TCF-1pos stem- like CTL are recruited to and retained in these niches and directed to interact with DC3, and we will explore the mechanism sby which the niches are formed in response to PD-1 blockade.

项目摘要 暴露于免疫系统不能迅速清除的致病病毒会导致慢性病毒感染。 针对此类病毒的细胞毒性T细胞（CTL）应答逐渐采用表观遗传学固定的功能低下的免疫应答。 状态通常被称为T细胞耗竭，这被认为是防止免疫病理组织 由抗病毒CTL驱动的持续高水平炎症造成的损伤。类似的适应形式发生在 CTL应答恶性肿瘤，并导致增加免疫肿瘤耐受性。无论是 慢性病毒感染和恶性肿瘤，抗体阻断所谓的免疫检查点，包括 在活化的CTL上表达的抑制性PD-1受体通常可以恢复耗尽的CTL应答。然而，在这方面， 这种恢复发生的机制还不完全清楚。 在单细胞水平上，在耗尽的T细胞应答的效应位点处的CTL群体由干细胞样CTL组成。 表达转录因子TCF-1的记忆细胞以及瞬时表达TCF-1的TCF-1 neg效应样细胞 在最终采取功能减退状态之前， 终末分化最近发现，PD-1阻断不能恢复终末细胞的功能， 分化的细胞，但主要作用于TCF-1 pos干细胞样细胞，并导致它们分裂，失去TCF-1 表达，并产生介导抗病毒或抗肿瘤活性的高度增殖性瞬时效应子样亚群。 肿瘤控制 在该项目的前期工作中，我们已经描述了趋化因子受体CXCR 6的关键作用， 优化瞬时效应子样CTL与常规树突状细胞的罕见活化状态的相互作用 称为DC 3，其将IL-15反式呈递给CTL以促进其在肿瘤组织中的存活和积累。DC3 在肿瘤间质的微血管周围密集聚集，形成血管周围龛，我们认为这可能 作为慢性炎症部位CTL应答的关键守门人。我们建议测试 假设这些血管周围的小生境也是维持TCF-1 pos干细胞样CTL的位点， 肿瘤组织，并将其转化为效应样细胞。我们将使用高度多路组织成像技术 的整体肿瘤和活体显微镜，以确定趋化性的指导线索，TCF-1阳性干细胞， 像CTL一样被招募并保留在这些小生境中，并被引导与DC 3相互作用，我们将探索 通过其响应于PD-1阻断而形成小生境的机制。