The Role of CD5 in Tumor Immunity

CD5在肿瘤免疫中的作用

• 批准号: 10428617
• 负责人: Eynav Yafit Klechevsky
• 金额: $ 35.31万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10428617
• 关键词: Address; Affect; Antigen Presentation; Antigen-Presenting Cells; Binding; Blood; CRISPR/Cas technology; Cancer Vaccines; Cell physiology; Cells; Cellular Immunity; Cellular biology; Classification; Complement; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Ensure; Generations; Genes; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunologic Memory; Immunologic Surveillance; Immunomodulators; Immunotherapy; Interferon Type II; Intervention; Laboratories; Laser Scanning Confocal Microscopy; Lead; MHC Class I Genes; Malignant Neoplasms; Mediating; Melanoma Cell; Minority; Modification; Mouse Strains; Mus; Myelogenous; Pathway interactions; Patients; Phenotype; Play; Production; Publishing; Regulation; Regulatory T-Lymphocyte; Resistance; Role; Shapes; Signal Transduction; Skin; System; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Tumor Immunity; anti-CTLA4; anti-PD-1; anti-tumor immune response; cancer cell; cancer therapy; cancer vaccination; checkpoint therapy; cytokine; cytotoxic; effector T cell; experimental study; extracellular; fibrosarcoma; human tissue; immune checkpoint blockade; improved; in vivo; insight; lymph nodes; melanoma; mouse model; neoantigens; novel; pre-clinical; prevent; receptor; recruit; response; single-cell RNA sequencing; stem cell differentiation; stem cells; treatment response; tumor; vaccine response

ABSTRACT Dendritic cells (DCs) play critical roles in the regulation of anti-tumor immune responses. In both mice and humans, DCs consist of distinct subsets with intrinsic differences that lead to functional specialization in the generation of immunity. Compared to mice, little is known about the functional classification of human tissue- resident DCs, and how subset distribution is altered in disease. My laboratory has published pioneering studies on the identification and functional characterization of human DC subsets with respect to their control of cellular and humoral immunity. This application focuses on our recent discovery of a new human DC subset that is delineated by CD5 expression and that we discovered initially in human skin, blood and lymph nodes. CD5+ DCs are present in both mice and humans. They efficiently polarize T cells into helper and cytotoxic responses, and their number is reduced in melanoma affected compared to healthy tissue. Preliminary data using human DCs and pre-clinical mouse models are provided to demonstrate that CD5 is a critical molecule on DCs that sustains T cell activation and tumor rejection in vivo. Although the survival of advanced melanoma patients has been extended by interventions that enhance T cell activation, the response is limited to a minority of patients. Thus, we hypothesize that harnessing the CD5 costimulatory system on DCs will contribute towards the generation of a broad T cell response and immunological memory that is required to completely eliminate melanoma cells. To address this hypothesis, we will 1) harness novel murine models developed in our laboratory to define the requirement of CD5 on either DCs or T cells in tumor immunity, anti-tumor vaccination and in shaping response to checkpoint blockade therapy; 2) determine the molecular interactions underlying the activation and anti-tumor T responses by CD5+ DCs; 3) determine whether the distribution and the function of the CD5+ DCs is restored in patients with melanoma that respond to checkpoint blockade therapy. These studies will advance our understanding of a novel mechanism by which dendritic cells function to target cancer cells and will provide a rationale for harnessing CD5+ DC biology in a therapeutic setting.

摘要 树突状细胞（Dendritic cells，DC）在抗肿瘤免疫应答的调节中起关键作用。在小鼠和 在人类中，DC由具有内在差异的不同亚群组成，这些差异导致DC中的功能特化。 免疫力的产生。与小鼠相比，我们对人体组织的功能分类知之甚少- 居民DC，以及疾病中亚群分布如何改变。我的实验室发表了一些开创性的研究 对人DC亚群的鉴定和功能表征， 和体液免疫。本申请集中于我们最近发现的一种新的人类DC亚群， 我们最初在人类皮肤、血液和淋巴结中发现了这种现象。CD5+ DC 在老鼠和人类身上都存在。它们有效地将T细胞转化为辅助和细胞毒性反应， 与健康组织相比，它们的数量在受影响的黑素瘤中减少。使用人DC的初步数据 提供了临床前小鼠模型以证明CD 5是DC上的关键分子， 体内T细胞活化和肿瘤排斥。 尽管通过增强T细胞免疫应答的干预措施延长了晚期黑色素瘤患者的生存期， 激活后，反应仅限于少数患者。因此，我们假设利用CD 5 DC上的共刺激系统将有助于产生广泛的T细胞应答， 免疫记忆，需要完全消除黑色素瘤细胞。为了解决这个 假设，我们将1）利用我们实验室开发的新型小鼠模型来定义 DC或T细胞上的CD 5在肿瘤免疫、抗肿瘤疫苗接种和形成对检查点的反应中的作用 阻断治疗; 2）确定活化和抗肿瘤T应答的分子相互作用 3）确定CD 5 + DCs的分布和功能是否在CD 5 + DCs患者中恢复。 对检查点阻断疗法有反应的黑素瘤。 这些研究将促进我们对树突状细胞发挥靶向作用的新机制的理解。 癌细胞，并将提供在治疗环境中利用CD 5 + DC生物学的基本原理。