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细胞在自适应免疫系统中起着核心作用，并因T细胞受体（TCR）而被激活识别抗原呈现细胞的主要相容性复合物（MHC）上的抗原（APC）。为了完全实现T细胞效应子功能，参与提供了必不可少的“第二信号” APC上的T细胞共刺激受体CD28与其B7配体（CD80/CD86）。我们最近证明了T细胞和APC上的唾液酸该死的CD28与CD80/CD86结合，并去除用唾液酸酶增强T细胞增殖的唾液酸。去除唾液酸也与编程细胞死亡蛋白-1（αPD1）检查点抑制剂阻断，用于耗尽的T细胞的功能复兴。在这个项目，我们将开发双功能αPD1-硅化酶结合物，这些酶有望结合的好处 PD1封锁，去除CD28的唾液酸配体以促进与B7配体的互动并增强 T细胞激活。我们将评估癌症动物模型中的这些试剂的治疗潜力充满疲惫的T细胞并抑制癌症的进展。