Role of tumor microenvironment-derived cholesterol in CD8+ T-cell exhaustion

肿瘤微环境衍生的胆固醇在 CD8 T 细胞耗竭中的作用

基本信息

批准号：
10251255
负责人：
Qing Yi
金额：
$ 42.55万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10251255
关键词：
Adoptive Cell Transfers CD8-Positive T-Lymphocytes Cancer Patient Cell physiology Cells Cellular Metabolic Process Cholesterol Clinical Colon Carcinoma Colonic Neoplasms Cytotoxic T-Lymphocytes Human Immune Immunotherapy In complete remission Malignant Neoplasms Metabolic Methods Modeling Multiple Myeloma Mus Nivolumab Normal tissue morphology PD-1/PD-L1 Patients Role Sampling T-Lymphocyte Testing Toxic effect Tumor Tissue Tumor-Derived anti-PD1 antibodies antitumor effect base cancer immunotherapy cancer therapy clinical efficacy cytotoxic CD8 T cells effector T cell exhaust exhaustion immune checkpoint blockade improved melanoma neoplastic cell new therapeutic target novel phase 1 study programmed cell death ligand 1 programmed cell death protein 1 receptor response success therapeutic development tumor tumor microenvironment

项目摘要

Project Summary Recently we discovered that cholesterol metabolically reprograms tumor-infiltrating T cells so that they become exhausted. Our unpublished, preliminary studies showed that tumor tissues have a much higher cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in tumor-infiltrating T cells have significantly higher cholesterol content than PD-1med2B4med cells, which in turn have significantly higher cholesterol content than PD-1low2B4low cells in different murine tumor models. The same was observed in human multiple myeloma and colon tumor samples of. We also showed that the PD-1high2B4high CD8+ T cells have significantly higher LAG-3 and TIM-3 (other T-cell exhaustion markers) expression than PD-1med2B4med cells, and the PD-1med2B4med cells have significantly higher LAG-3 and TIM-3 expression than PD-1low2B4low cells. Consistently, sorted PD-1high2B4high CD8+ T cells displayed much weaker cytolytic activity against target tumor cells than PD-1med2B4med CD8+ T cells. Adding cholesterol to the culture of tumor-specific CD8+ T cells upregulated their expression of PD-1 and other exhaustion markers and reduced their cytolytic activity. Conversely, reducing cholesterol content in sorted PD-1high2B4high tumor-infiltrating CD8+ T cells downregulated their expression of PD-1 and other exhaustion markers and enhanced their cytolytic activity. Based on these novel findings, we hypothe size that the tumor and its microenvironment induce effector T -cell exhaustion by using cholesterol to metabolically reprogram and upregulate the expression of immune inhibitory receptors and exhaustion markers on CD8+ cells. Aim 1 will determine the mechanisms underlying cholesterol-induced CD8+ T-cell exhaustion, and Aim 2 will reprogram CD8+ T-cell metabolism and/or the tumor microenvironment to enhance the antitumor effects of tumor-specific CD8+ T cells. Completing this project will give us in-depth understanding of the mechanisms involved in how tumor -derived cholesterol metabolically repr ograms tumor- infiltrating T cells so that they become exhausted. Understanding the mechanisms will allow us and others to identify novel therapeutic targets and develop new methods to improve the efficacy of T cell- or immune checkpoint blockade-based immunotherapy in cancer.

项目概要最近我们发现胆固醇通过代谢重新编程肿瘤浸润 T 细胞，使其变得精疲力尽。我们未发表的初步研究表明，肿瘤组织具有更高的与正常组织相比胆固醇含量，以及肿瘤浸润T细胞中PD-1high2B4high CD8+ T细胞细胞的胆固醇含量显着高于 PD-1med2B4med 细胞，而后者的胆固醇含量显着高于 PD-1med2B4med 细胞。在不同的小鼠肿瘤模型中，胆固醇含量高于PD-1low2B4low细胞。观察到同样的情况在人类多发性骨髓瘤和结肠肿瘤样本中。我们还表明 PD-1high2B4high CD8+ T 细胞与 PD-1med2B4med 相比，LAG-3 和 TIM-3（其他 T 细胞耗竭标记物）表达显着更高细胞中，PD-1med2B4med 细胞的 LAG-3 和 TIM-3 表达量显着高于 PD-1low2B4low 细胞。一致地，分选的 PD-1high2B4high CD8+ T 细胞对靶标表现出较弱的细胞溶解活性肿瘤细胞高于 PD-1med2B4med CD8+ T 细胞。在肿瘤特异性 CD8+ T 细胞培养物中添加胆固醇上调 PD-1 和其他耗竭标志物的表达并降低其细胞溶解活性。相反，降低分选的 PD-1high2B4high 肿瘤浸润 CD8+ T 细胞中的胆固醇含量下调它们的 PD-1 和其他耗竭标志物的表达并增强了它们的细胞溶解活性。基于这些新颖的发现，我们假设肿瘤的大小及其微环境通过以下方式诱导效应 T 细胞耗竭使用胆固醇进行代谢重编程并上调免疫抑制受体的表达， CD8+ 细胞上的耗竭标记。目标 1 将确定胆固醇诱导 CD8+ 的潜在机制 T 细胞耗竭，目标 2 将重新编程 CD8+ T 细胞代谢和/或肿瘤微环境增强肿瘤特异性CD8+ T细胞的抗肿瘤作用。完成这个项目将使我们深入了解肿瘤源性胆固醇如何代谢复制肿瘤的机制渗透 T 细胞，使它们变得精疲力尽。了解这些机制将使我们和其他人能够确定新的治疗靶点并开发新方法来提高 T 细胞或免疫的功效基于检查点封锁的癌症免疫疗法。