Merck & Co., Inc., Palo Alto, California.
Charles River Laboratories, Insourcing Solutions, Palo Alto, California.
Cancer Immunol Res. 2018 Oct;6(10):1199-1211. doi: 10.1158/2326-6066.CIR-17-0632. Epub 2018 Aug 28.
GITR is a costimulatory receptor currently undergoing phase I clinical trials. Efficacy of anti-GITR therapy in syngeneic mouse models requires regulatory T-cell depletion and CD8 T-cell costimulation. It is increasingly appreciated that immune cell proliferation and function are dependent on cellular metabolism. Enhancement of diverse metabolic pathways leads to different immune cell fates. Little is known about the metabolic effects of GITR agonism; thus, we investigated whether costimulation via GITR altered CD8 T-cell metabolism. We found activated, GITR-treated CD8 T cells upregulated nutrient uptake, lipid stores, glycolysis, and oxygen consumption rate (OCR) Using MEK, PI3Kδ, and metabolic inhibitors, we show increased metabolism is required, but not sufficient, for GITR antibody (DTA-1)-induced cellular proliferation and IFNγ production. In an model of PD-L1-induced CD8 T-cell suppression, GITR agonism alone rescued cellular metabolism and proliferation, but not IFNγ production; however, DTA-1 in combination with anti-PD-1 treatment increased IFNγ production. In the MC38 mouse tumor model, GITR agonism significantly increased OCR and IFNγ and granzyme gene expression in both tumor and draining lymph node (DLN) CD8 T cells , as well as basal glycolysis in DLN and spare glycolytic capacity in tumor CD8 T cells. DLN in GITR-treated mice showed significant upregulation of proliferative gene expression compared with controls. These data show that GITR agonism increases metabolism to support CD8 T-cell proliferation and effector function , and that understanding the mechanism of action of agonistic GITR antibodies is crucial to devising effective combination therapies. .
GITR 是一种共刺激受体，目前正在进行 I 期临床试验。在同基因小鼠模型中，抗 GITR 治疗的疗效需要调节性 T 细胞耗竭和 CD8 T 细胞共刺激。人们越来越认识到，免疫细胞的增殖和功能依赖于细胞代谢。增强各种代谢途径会导致不同的免疫细胞命运。关于 GITR 激动剂的代谢影响知之甚少；因此，我们研究了 GITR 共刺激是否改变了 CD8 T 细胞代谢。我们发现，激活的、经 GITR 处理的 CD8 T 细胞上调了营养物质摄取、脂质储存、糖酵解和耗氧量（OCR）。使用 MEK、PI3Kδ 和代谢抑制剂，我们表明增加代谢是必需的，但不是充分的，用于 GITR 抗体（DTA-1）诱导的细胞增殖和 IFNγ 产生。在 PD-L1 诱导的 CD8 T 细胞抑制模型中，GITR 激动剂单独即可挽救细胞代谢和增殖，但不能挽救 IFNγ 产生；然而，DTA-1 与抗 PD-1 治疗联合使用可增加 IFNγ 产生。在 MC38 小鼠肿瘤模型中，GITR 激动剂显著增加了 OCR 和 IFNγ 和颗粒酶基因表达在肿瘤和引流淋巴结（DLN）CD8 T 细胞中，以及 DLN 中的基础糖酵解和肿瘤 CD8 T 细胞中的备用糖酵解能力。与对照组相比，GITR 处理小鼠的 DLN 显示出明显的增殖基因表达上调。这些数据表明，GITR 激动剂增加代谢以支持 CD8 T 细胞增殖和效应功能，并且了解激动性 GITR 抗体的作用机制对于设计有效的联合治疗方法至关重要。
