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

项目摘要 最近，我们发现胆固醇通过代谢重编程肿瘤浸润性T细胞， 变得筋疲力尽我们未发表的初步研究表明，肿瘤组织具有高得多的 胆固醇含量与正常组织相比，肿瘤浸润性T细胞中PD-1高2B 4高CD 8 + T细胞 细胞具有比PD-1 med 2B 4 med细胞显著更高的胆固醇含量，而PD-1 med 2B 4 med细胞又具有显著更高的胆固醇含量。 在不同的小鼠肿瘤模型中，胆固醇含量高于PD-1低2B 4低细胞。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。我们还发现PD-1高2B 4高CD 8 + T细胞 LAG-3和TIM-3（其他T细胞耗竭标志物）的表达显著高于PD-1 med 2B 4 med PD-1 med 2B 4 med细胞的LAG-3和TIM-3表达显著高于PD-1 low 2B 4low细胞 细胞一致地，分选的PD-1高2B 4高CD 8 + T细胞显示出弱得多的针对靶细胞的细胞溶解活性。 PD-1 med 2B 4 med CD 8 + T细胞。向肿瘤特异性CD 8 + T细胞的培养物中添加胆固醇 上调它们的PD-1和其它耗竭标志物的表达并降低它们的细胞溶解活性。 相反，降低分选的PD-1高2B 4高肿瘤浸润性CD 8 + T细胞中的胆固醇含量下调 其表达PD-1和其它耗竭标志物并增强其细胞溶解活性。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细胞耗竭 使用胆固醇来代谢重编程和上调免疫抑制受体的表达， CD 8+细胞的耗竭标志物。目的1将确定胆固醇诱导的CD 8 + T细胞的机制。 Aim 2将重新编程CD 8 + T细胞代谢和/或肿瘤微环境， 增强肿瘤特异性CD 8 + T细胞的抗肿瘤作用。完成这个项目将使我们深入了解 了解肿瘤来源的胆固醇代谢如何反映肿瘤的机制， 浸润T细胞使其衰竭。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的方法来提高T细胞或免疫系统的功效。 基于检查点阻断的癌症免疫疗法。

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 Our unpublished, preliminary studies showed that tumor tissues have a much higher cholesterol content compared with normal tissues, and the PD-1high2B4high CD8+ T cells in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