The Role of CD5 in Tumor Immunity

CD5在肿瘤免疫中的作用

基本信息

批准号：
10053153
负责人：
Eynav Yafit Klechevsky
金额：
$ 36.03万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10053153
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 Myeloproliferative disease 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

项目摘要

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.

抽象的树突状细胞（DC）在抗肿瘤免疫反应的调节中发挥着关键作用。在小鼠和人类中，树突状细胞由不同的子集组成，这些子集具有内在的差异，导致功能专门化免疫力的产生。与小鼠相比，我们对人体组织的功能分类知之甚少—— 常驻 DC，以及疾病中子集分布如何改变。我的实验室发表了开创性研究人类 DC 子集的识别和功能表征及其对细胞的控制和体液免疫。该应用重点关注我们最近发现的一个新的人类 DC 子集，即我们最初在人类皮肤、血液和淋巴结中发现了 CD5 表达。 CD5+ DC 存在于小鼠和人类中。它们有效地将 T 细胞极化为辅助反应和细胞毒性反应，并且与健康组织相比，在受影响的黑色素瘤中它们的数量减少。使用人类 DC 的初步数据提供临床前小鼠模型来证明 CD5 是 DC 上维持维持的关键分子体内 T 细胞激活和肿瘤排斥。尽管通过增强 T 细胞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 CD5 DC 上的共刺激系统将有助于产生广泛的 T 细胞反应完全消除黑色素瘤细胞所需的免疫记忆。为了解决这个问题假设，我们将 1）利用我们实验室开发的新型小鼠模型来定义以下要求： DC 或 T 细胞上的 CD5 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封锁疗法； 2) 确定激活和抗肿瘤 T 反应背后的分子相互作用由 CD5+ DC 引起； 3) 确定CD5+ DCs在患者体内的分布和功能是否恢复对检查点阻断疗法有反应的黑色素瘤。这些研究将增进我们对树突状细胞靶向作用的新机制的理解癌细胞，并将为在治疗环境中利用 CD5+ DC 生物学提供理论依据。