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

项目摘要 免疫检查点抑制剂（ICI）通过阻断各种调节轴来引发抗肿瘤免疫， 通常抑制T淋巴细胞靶向肿瘤细胞的能力。虽然ICI疗法 通过为其他难治性肿瘤提供治疗选择，彻底改变了肿瘤学领域， 一部分患者经历了有意义的临床获益，而不良炎症和 经常发生自身免疫毒性。为了改善治疗效果， 建立生物标志物，可以预测治疗，以及对特定的不良反应， ICIs。最近FDA批准的ICI是一种靶向淋巴细胞活化的单克隆抗体 基因-3（anti-LAG 3，relatlimab），在多种免疫细胞类型上表达。LAG 3的知识 其作用机制主要限于其在调节T细胞功能中的内在作用。因此，在本发明中， 了解LAG 3在其他免疫细胞中的内在作用，这些免疫细胞对编程抗- 肿瘤免疫以及病理性炎症应该提供重要的见解如何抗- LAG 3引起有益的治疗反应和不良的患者反应。该项目旨在填补这一 关键的知识差距基于我们的两个关键的初步调查结果。首先，Lag 3在以下方面起着内在的作用： 小鼠抗原呈递树突状细胞（DC），以限制其激活和引发初始T细胞的能力， 细胞增殖并产生效应功能。第二，具有血浆LAG 3 缺乏会降低循环中IL-10的水平，并增加心血管疾病的风险。 这形成了我们的中心假设的基础，即Lag 3缺陷型DC具有增强的能力， 致敏肿瘤特异性效应T细胞，导致肿瘤生长减少，但也不利血管生成。 炎症这将使用两种新的和互补的基因组编辑的小鼠模型进行测试， DC条件Lag 3表达式。具体而言，目标1将确定Lag 3在以下方面的DC固有作用： 在黑色素瘤模型中引发效应T细胞和抗肿瘤免疫，而Aim 2将分析如何 高胆固醇血症和Lag 3缺乏之间的相互作用影响ICI癌症治疗 有效性以及诱导的不良心血管炎症。为达致这些目标，我们会 为我们对临床相关免疫系统的机械理解增加了一个新的维度， 靶向Lag 3，鉴定潜在的生物标志物以预测对抗LAG 3治疗的反应性，并建立 未来研究的实验框架，以制定策略，最大限度地减少心血管不良反应 通过阻断LAG 3引起的病理，同时维持抗肿瘤免疫。

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.