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

项目摘要 最近我们发现，胆固醇会对肿瘤浸润性T细胞进行新陈代谢，从而使它们 变得筋疲力尽。我们未发表的初步研究表明，肿瘤组织中有更高的 胆固醇含量与正常组织比较，肿瘤浸润性T细胞中PD-1高2B4高CD8+T细胞 细胞的胆固醇含量显著高于PD-1Med2B4med细胞，后者又显著 在不同的小鼠肿瘤模型中，胆固醇含量高于PD-1low2B4低细胞。观察到的情况也是如此 在人类多发性骨髓瘤和结肠癌标本中。我们还发现PD-1High 2B4高CD8+T细胞 有显著高于PD-1med2B4med的LAG-3和TIM-3(其他T细胞衰竭标志物)的表达 PD-1med2B4med细胞的LAG-3和Tim-3表达显著高于PD-1low2B4low 细胞。一致地，分选的PD-1High2B4高CD8+T细胞对靶细胞的杀伤活性要弱得多 肿瘤细胞多于PD-1Med2B4介导的CD8+T细胞。在肿瘤特异性CD8+T细胞培养中添加胆固醇 上调PD-1和其他力竭标志物的表达，降低其杀伤细胞的活性。 相反，降低分选的PD-1High2B4高肿瘤浸润性CD8+T细胞中的胆固醇含量下调 它们表达PD-1和其他力竭标志物，并增强其杀伤细胞的活性。基于这些 新的发现，我们假设肿瘤及其微环境通过以下方式诱导效应T细胞耗尽 利用胆固醇代谢重新编程和上调免疫抑制受体和 CD8+细胞上的耗竭标志物。目标1将确定胆固醇诱导CD8+的潜在机制 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 增强肿瘤特异性CD8+T细胞的抗肿瘤作用。完成这个项目将给我们带来深入的 了解肿瘤源性胆固醇代谢与肿瘤相关的机制 渗透T细胞，使它们变得精疲力竭。了解这些机制将使我们和其他人能够 发现新的治疗靶点并开发新方法来提高T细胞或免疫的疗效 癌症中基于检查点封锁的免疫治疗。

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 Our unpublished, preliminary studies showed that tumor tissues have a much higher cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in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