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 Our unpublished, preliminary studies showed that tumor tissues have a much higher cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in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.

项目摘要最近，我们发现胆固醇代谢对肿瘤浸润的T细胞进行重新编程，以便它们变得精疲力尽。我们未发表的初步研究表明，肿瘤组织的较高与正常组织相比，胆固醇含量，以及肿瘤浸润T的PD-1HIGH2B4-HIGH CD8+ T细胞细胞的胆固醇含量明显高于PD-1Med2B4Med细胞，而PD-1Med2B4Med细胞又具有显着的在不同的鼠肿瘤模型中，胆固醇含量高于PD-1LOW2B4LOW细胞。观察到一样在人类多发性骨髓瘤和结肠肿瘤样品中。我们还表明PD-1HIGH2B4高CD8+ T细胞与PD-1Med2B4Med相比，LAG-3和TIM-3（其他T细胞耗尽标记）的表达明显更高细胞，PD-1Med2B4Med细胞的滞后3和TIM-3表达明显高于PD-1LOW2B4LOW 细胞。一致地，分类的PD-1HIGH2B4HIGH CD8+ T细胞显示出针对靶的细胞溶解活性较弱肿瘤细胞比PD-1Med2B4Med CD8+ T细胞。将胆固醇添加到肿瘤特异性CD8+ T细胞的培养物中上调了它们的PD-1和其他精疲力尽标记，并降低了其溶溶活性。相反，在排序的PD-1HIGH2B4HIGH肿瘤渗透CD8+ T细胞中降低胆固醇含量下调它们的PD-1和其他疲惫标记物的表达并增强了其细胞溶解活性。基于这些新发现，我们假设肿瘤及其微环境通过使用胆固醇代谢重新编程并上调免疫抑制受体的表达和 CD8+细胞上的耗尽标记。 AIM 1将确定胆固醇诱导的CD8+的机制 T细胞耗尽，AIM 2将重新编程CD8+ T细胞代谢和/或肿瘤微环境至增强肿瘤特异性CD8+ T细胞的抗肿瘤作用。完成该项目将使我们深入了解肿瘤衍生的胆固醇如何代谢肿瘤涉及的机制渗透T细胞，使它们筋疲力尽。了解这些机制将使我们和其他人得以确定新型的治疗靶标并开发新方法以提高T细胞或免疫的功效基于检查点封锁的癌症免疫疗法。