Understanding how the interaction between Lag3 deficiency and hypercholesterolemia impact anti-tumor immunity and cardiovascular disease in a melanoma model

了解 Lag3 缺乏与高胆固醇血症之间的相互作用如何影响黑色素瘤模型中的抗肿瘤免疫和心血管疾病

• 批准号: 10637369
• 负责人: ADAM J ADLER
• 金额: $ 27.1万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637369
• 关键词: Address; Adverse event; Age; Antigen Presentation; Aorta; Autoimmune; Biological Markers; Biology; Bone Marrow; CD4 Positive T Lymphocytes; CTLA4 gene; Cardiovascular Diseases; Cardiovascular Pathology; Cardiovascular system; Cells; Cholesterol; Clinical; Dendritic Cells; Dimensions; Event; Exhibits; FDA approved; Future; Gene Activation; Glean; High Density Lipoprotein Cholesterol; Human; ITGAX gene; Immune; Immune checkpoint inhibitor; Immune system; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Interleukin-10; Knock-in; Knock-in Mouse; Knock-out; Knockout Mice; Knowledge; Lipids; Lymphocyte Activation; Malignant Neoplasms; Metastatic Melanoma; Modality; Modeling; Monoclonal Antibodies; Multi-Ethnic Study of Atherosclerosis; Mus; Myocardial Infarction; Myocarditis; Nivolumab; Oncology; Participant; Pathologic; Patients; Pharmaceutical Preparations; Plasma; Play; Proliferating; Protein Deficiency; Proteins; Regulatory T-Lymphocyte; Reporting; Risk; Role; Serious Adverse Event; Skin Cancer; Smoking; T cell infiltration; T cell therapy; T-Lymphocyte; TNF gene; Testing; Therapeutic; Transplantation; Treatment Efficacy; Treatment outcome; Tumor Immunity; Unresectable; Variant; Wild Type Mouse; anti-PD-1; anti-PD-L1; antitumor effect; autoimmune toxicity; biomarker identification; cancer immunotherapy; cancer therapy; cardiovascular disorder risk; cell type; checkpoint therapy; clinical development; clinically relevant; cytokine; effector T cell; experience; genome editing; high risk; hypercholesterolemia; improved; insight; melanoma; mortality risk; mouse model; neoplastic cell; novel; novel therapeutics; patient biomarkers; patient response; patient subsets; potential biomarker; pre-clinical; predict responsiveness; programmed cell death ligand 1; therapeutic target; tumor; tumor growth; vascular inflammation; virtual

Project Summary Immune checkpoint inhibitors (ICIs) elicit anti-tumor immunity by blocking various regulatory axes that normally dampen the capacity of T lymphocytes to target tumor cells. While ICI therapies have revolutionized the field of oncology by providing treatment options for otherwise intractable tumors, only a subset of patients experience meaningful clinical benefits, while adverse inflammatory and autoimmune toxicities often occur. To improve treatment outcomes, efforts have been underway to establish biomarkers that can predict both therapeutic, as well as adverse responsiveness to particular ICIs. The most recently FDA-approved ICI is a monoclonal antibody that targets Lymphocyte Activation Gene-3 (anti-LAG3, relatlimab), which is expressed on many immune cell types. Knowledge of LAG3's mechanism of action is mainly limited to its intrinsic role in regulating the function of T cells. Thus, understanding the intrinsic role of LAG3 in other immune cells that are critical for programming anti- tumor immunity as well as pathologic inflammation should provide important insights into how anti- LAG3 elicits both beneficial therapeutic, and adverse patient responses. This project seeks to fill this critical knowledge gap based on our two key preliminary findings. First, Lag3 plays an intrinsic role in murine antigen presenting dendritic cells (DCs) to limit their activation and capacity to prime naive T cells to proliferate and develop effector functionality. Second, human patients with plasma LAG3 deficiency have decreased levels of circulating IL-10, and increased risk for cardiovascular disease. This forms the basis of our central hypothesis that Lag3-deficient DCs have an enhanced capacity to prime tumor-specific effector T cells, leading to reduced tumor growth, but also adverse vascular inflammation. This will be tested using two novel and complimentary genome-edited mouse models of DC-conditional Lag3 expression. Specifically, Aim 1 will determine the DC-intrinsic role of Lag3 in priming effector T cells and anti-tumor immunity in a melanoma model, while Aim 2 will analyze how the interaction between hypercholesterolemia and Lag3 deficiency impacts both ICI cancer therapy efficacy as well as induced adverse cardiovascular inflammation. In accomplishing these aims, we will add a new dimension to our mechanistic understanding of the clinically relevant immunotherapeutic target Lag3, identify potential biomarkers to predict responsiveness to anti-LAG3 therapy, and establish an experimental framework for future studies to develop strategies to minimize adverse cardiovascular pathology caused by blocking LAG3, while maintaining anti-tumor immunity.

项目摘要 免疫检查点抑制剂（ICIS）通过阻止各种调节轴来引起抗肿瘤免疫力 通常会抑制T淋巴细胞对靶向肿瘤细胞的能力。 ICI疗法有 仅通过为其他棘手的肿瘤提供治疗选择，彻底改变了肿瘤学领域 一部分患者经历有意义的临床益处，而炎症和 经常发生自身免疫性毒性。为了改善治疗结果，正在努力 建立可以预测治疗性和对特定的不良反应的生物标志物 ICIS。最近，FDA批准的ICI是一种靶向淋巴细胞激活的单克隆抗体 Gene-3（抗LAG3，Relatlimab），在许多免疫细胞类型上表达。对lag3的知识 作用机理主要限于其在调节T细胞功能中的内在作用。因此， 了解lag3在其他免疫细胞中的内在作用，这对于编程抗 - 肿瘤免疫以及病理炎症应提供重要的见解 lag3引起有益的治疗和不良患者反应。这个项目旨在填补这个 基于我们的两个关键初步发现的批判知识差距。首先，lag3在 鼠抗原呈现树突状细胞（DC），以限制其活化的能力 细胞增殖和发展效应子功能。第二，血浆lag3患者 缺乏率降低了循环IL-10的水平，并增加了心血管疾病的风险。 这构成了我们中心假设的基础，即lag3缺陷DC具有增强的能力 主要肿瘤特异性效应T细胞，导致肿瘤生长降低，但也不良血管 炎。这将使用两个新颖和免费的基因组编辑的小鼠模型进行测试 直流条件滞后3的表达。具体而言，AIM 1将确定lag3在 黑色素瘤模型中的启动效应T细胞和抗肿瘤免疫力，而AIM 2将分析如何分析 高胆固醇血症与lag3缺乏症之间的相互作用会影响两种ICI癌症治疗 功效以及诱导的不良心血管炎症。在实现这些目标时，我们将 为我们对临床相关的免疫治疗性的机械理解添加一个新的维度 靶LAG3，确定潜在的生物标志物以预测对抗LAG3治疗的反应性，并确定 未来研究的实验框架，以制定最大程度地减少不良心血管的策略 在维持抗肿瘤免疫力的同时，由阻断滞后3引起的病理。