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Removing sialic acid ligands of CD28 to enhance T cell cancer immunotherapy

去除CD28的唾液酸配体以增强T细胞癌症免疫治疗

基本信息

批准号：
10668007
负责人：
JAMES C PAULSON
金额：
$ 22.63万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-17 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10668007
关键词：
Adaptive Immune System Animal Cancer Model Antibodies Antigen-Presenting Cells Antigens Binding Blocking Antibodies C-terminal CD28 gene CD80 gene CD86 gene CT26 CTLA4 gene Cells Clinical Colon Carcinoma ERBB2 gene Engineering Epidermal Growth Factor Receptor Excision Flow Cytometry Gene Activation Green Fluorescent Proteins Human ITIM Immune Immune checkpoint inhibitor Immunoglobulins Immunologics In Vitro Lectin Leucocytic infiltrate Leukocytes Ligands Ligation Lymphocyte Activation Lymphocytic choriomeningitis virus MC38 Major Histocompatibility Complex Malignant Neoplasms Modeling Monitor Mucins Mus N-terminal Neoplasm Metastasis Neuraminidase Peptidyltransferase Play Polysaccharides Proteins Reagent Refractory Role Sialic Acids Signal Transduction Solid Neoplasm Source T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte T-Lymphocyte Subsets Therapeutic Therapeutic Effect Time Tumor Immunity Tumor-associated macrophages Tyrosine anti-PD-1 anti-PD-L1 antibody-dependent cell cytotoxicity arm cancer cell cancer immunotherapy cancer infiltrating T cells checkpoint therapy chronic infection effector T cell epimerase exhaust exhaustion high dimensionality immune checkpoint immune checkpoint blockade immunogenic immunoregulation in vivo lymph nodes melanoma polyglycine programmed cell death ligand 1 programmed cell death protein 1 receptor response sialic acid binding Ig-like lectin sialylation sortase tumor tumor growth tumor progression

项目摘要

Summary T cells play a central role in the adaptive immune system and are activated in response to T cell receptor (TCR) recognition of antigen loaded on the major-histocompatibility complex (MHC) of antigen presenting cells (APCs). In order to fully achieve T cell effector function, an essential “second signal” is provided by engagement of the T cell costimulatory receptor CD28 with its B7 ligands (CD80/CD86) on the APC. We recently demonstrated that sialic acids on T cells and APCs dampen CD28 binding to CD80/CD86 and that removal of sialic acids with sialidase enhances T cell proliferation. Sialic acid removal is also synergistic with programmed cell death protein-1 (αPD1) checkpoint inhibitor blockade for functional revival of exhausted T cells. In this project, we will develop bifunctional αPD1-sialidase conjugates that are expected to combine the benefits of PD1 blockade with removal of sialic acid ligands of CD28 to promote engagement with B7 ligands and enhance T cell activation. We will evaluate these reagents in animal models of cancer for their therapeutic potential to invigorate exhausted T cells and suppress cancer progression.

概括 T 细胞在适应性免疫系统中发挥核心作用，并响应 T 细胞受体 (TCR) 而被激活识别抗原呈递细胞主要组织相容性复合体 (MHC) 上负载的抗原（装甲运兵车）。为了充分实现T细胞效应功能，接合提供了重要的“第二信号” APC 上的 T 细胞共刺激受体 CD28 及其 B7 配体 (CD80/CD86)。我们最近证明 T 细胞和 APC 上的唾液酸会抑制 CD28 与 CD80/CD86 的结合，并且去除唾液酸与唾液酸酶可增强 T 细胞增殖。唾液酸去除也与程序化有协同作用细胞死亡蛋白-1 (αPD1) 检查点抑制剂阻断可恢复耗尽的 T 细胞的功能。在这个项目中，我们将开发双功能 αPD1-唾液酸酶缀合物，预计将结合以下优点：通过去除 CD28 的唾液酸配体来阻断 PD1，以促进与 B7 配体的结合并增强 T 细胞激活。我们将在癌症动物模型中评估这些试剂的治疗潜力激活耗尽的 T 细胞并抑制癌症进展。