Augmenting T cell activity to weak tumor antigens and reversing myeloid cell-mediated T cell inhibition

增强 T 细胞对弱肿瘤抗原的活性并逆转骨髓细胞介导的 T 细胞抑制

• 批准号: 9669010
• 负责人: Eduardo V Davila
• 金额: $ 36.65万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9669010
• 关键词: Affinity; Antigens; Antitumor Response; Avidity; Binding; Brain Neoplasms; Cancer Vaccines; Cell Survival; Cell physiology; Cell surface; Cells; Cellular immunotherapy; Clinical; Clinical Trials; Cytotoxic T-Lymphocytes; Data; Exhibits; Gene-Modified; Goals; Human; In Vitro; Institution; Intracranial Melanoma; Kinetics; Ligands; Link; Major Histocompatibility Complex; Mediating; Molecular; Mus; Myeloid Cell Suppression; Myeloid Cells; Myeloid-derived suppressor cells; Patients; Property; Publishing; Receptor Activation; Receptor Signaling; Research; Resistance; Signal Transduction; Site; Skin; Stress; Survival Rate; T Cell Receptor Signaling Pathway; T cell response; T cell therapy; T-Cell Activation; T-Cell Receptor; T-Cell Receptor Genes; T-Lymphocyte; Testing; Time; Toll-like receptors; Translating; Tumor Antigens; base; cancer therapy; clinically relevant; clinically significant; cytotoxic CD8 T cells; effective therapy; engineered T cells; extracellular; immunogenic; improved; in vivo; insight; melanoma; neoantigens; neoplastic cell; novel; novel strategies; patient subsets; receptor; receptor binding; receptor expression; research clinical testing; response; subcutaneous; treatment strategy; tumor; vaccination strategy

Our long term goal is to develop a novel approach for treating established melanoma tumors by enhancing cytotoxic T cell responses towards weakly immunogenic and lowly expressed tumor antigens (TAgs) including neoantigens while simultaneously conferring T cells resistance to myeloid-derived suppressor cell (MDSC)– mediated suppression. In clinical trials, T cell-based immunotherapies have demonstrated tumor regression and increased survival rates. Yet despite these encouraging clinical results, durable antitumor responses are observed in only a subset of patients with advanced melanoma. This discrepancy stresses the need for more effective treatment strategies. T cell-based therapies are hindered in part by low T cell receptor (TCR) affinity and/or avidity and by the low expression of TAg on the tumor cell's surface. Additionally, the presence of MDSCs poses a major obstacle to generating effective and long-lived antitumor T cell responses. In our published and preliminary studies, activating MyD88 signaling in T cells, via toll like receptor engagement, augmented T cell responses and prolonged T cell survival. By fusing the CD8α (extracellular) to MyD88 (intracellular; CD8α:MyD88) molecule or by linking melanoma-reactive TCRs to MyD88 (TCR:MyD88) we have developed a novel platform that strongly activates MyD88 signaling in a TLR-independent, strictly TCR- dependent fashion. CD8α:MyD88 expression in T cells considerably amplifies responses to weak and suboptimal levels of TAg and in a TCR-dependent manner, and in preliminary studies has demonstrated the extraordinary property of differentiating MDSC's into cells that can enhance T cell responses. Importantly, the use of CD8α offers the unique feature in that it represents a `universal' approach to potentiating T cell responses, regardless of the patient's HLA type. Our central hypothesis is that T cells engineered to express a CD8α:MyD88 (or TCR:MyD88) will amplify TCR signals against a variety of weakly immunogenic or lowly expressed TAgs including neoantigens and reverse the suppressive activity of myeloid cell suppression, resulting in effective and long-lived antitumor responses. Aim 1 is to determine the molecular mechanisms by which MyD88 activation in T cells augments TCR signals. Through in vitro studies of human and mouse cells, we will define the molecular interactions through which MyD88 signaling augments TCR responses to tumor antigens of varying affinities. Aim 2 is determine the fate and antitumor efficacy of each CD8α:MyD88 and TCR:MyD88 T cells in mice with an established subcutaneous or intracranial melanoma tumor. Aim 3 is to ascertain the in vivo significance and define the mechanism(s) through which MyD88 signaling in T cells reverses myeloid cell's suppressive function. These studies are clinically significant as they have the potential to offer mechanistic insights as to how TCR responses can be amplified and, novel strategies for inhibiting and/or reversing MDSC function.

我们的长期目标是开发一种通过增强来治疗既定黑色素瘤肿瘤的新方法 细胞毒性T细胞对弱免疫原性和低表达肿瘤抗原（TAG）的反应包括 新抗原同时会议T细胞抗髓样衍生的抑制细胞（MDSC） - 介导的抑制。在临床试验中，基于T细胞的免疫疗法表明肿瘤消退 并提高生存率。但是要求这些令人鼓舞的临床结果，耐用的抗肿瘤反应是 仅在一部分患有晚期黑色素瘤的患者中观察到。这种差异强调需要更多 有效的治疗策略。基于T细胞的疗法部分受到低T细胞受体（TCR）亲和力的部分阻碍 和/或亲和力，并且通过肿瘤细胞表面上的标签表达低表达。另外，存在 MDSC构成了产生有效和长寿抗肿瘤T细胞反应的主要障碍。在我们的 发表和初步研究，通过像受体互动一样激活T细胞中的MyD88信号传导， 增强T细胞反应并延长T细胞存活。通过将CD8α（细胞外）融合到MyD88 （细胞内;CD8α：MyD88）分子或通过将黑色素瘤反应性TCR与MyD88（TCR：MyD88）联系起来，我们有 开发了一个新颖的平台，该平台强烈激活MyD88在TLR独立的，严格的TCR-中的信号传导 依赖的时尚。 CD8α：T细胞中MyD88的表达相当大多数放大器对弱和 标签的次优水平和以TCR依赖性的方式，在初步研究中表明 将MDSC的特性分化为可以增强T细胞反应的细胞的特性。重要的是， CD8α的使用提供了独特的功能，因为它代表了增强T细胞的“通用”方法 反应，无论患者的HLA类型如何。我们的中心假设是T细胞设计为 表达CD8α：MyD88（或TCR：MyD88）将扩大TCR信号 免疫原性或低表达的标签，包括新抗原，并逆转 髓样细胞抑制，导致有效且长寿命的抗肿瘤反应。目标1是 确定T细胞中MyD88激活增强TCR信号的分子机制。通过 对人类和小鼠细胞的体外研究，我们将定义MyD88的分子相互作用 信号传导增加了TCR对不同亲和力肿瘤抗原的反应。 AIM 2确定了命运和 每个CD8α的抗肿瘤效率：MyD88和TCR：MyD88 T细胞在小鼠中具有既定皮下或 颅内黑色素瘤肿瘤。目标3是确定体内意义并定义机制 T细胞中的MyD88信号传导逆转髓样细胞的抑制功能。这些研究是 临床意义很大，因为它们有潜力提供有关TCR反应的机理见解 放大和抑制MDSC功能的新型策略。