Armstrong Oxygen Biology Research Center and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Sci Adv. 2024 Aug 30;10(35):eadq2366. doi: 10.1126/sciadv.adq2366. Epub 2024 Aug 28.
Adoptive cell transfer (ACT) is a therapeutic strategy to augment antitumor immunity. Here, we report that ex vivo treatment of mouse CD8 T cells with dimethyloxalylglycine (DMOG), a stabilizer of hypoxia-inducible factors (HIFs), induced HIF binding to the genes encoding the costimulatory receptors CD81, GITR, OX40, and 4-1BB, leading to increased expression. DMOG treatment increased T cell killing of melanoma cells, which was further augmented by agonist antibodies targeting each costimulatory receptor. In tumor-bearing mice, ACT using T cells treated ex vivo with DMOG and agonist antibodies resulted in decreased tumor growth compared to ACT using control T cells and increased intratumoral markers of CD8 T cells (CD7, CD8A, and CD8B1), natural killer cells (NCR1 and KLRK1), and cytolytic activity (perforin-1 and tumor necrosis factor-α). Costimulatory receptor gene expression was also induced when CD8 T cells were treated with three highly selective HIF stabilizers that are currently in clinical use.
过继细胞转移（ACT）是一种增强抗肿瘤免疫的治疗策略。在这里，我们报告说，用二甲基草酰甘氨酸（DMOG）体外处理小鼠 CD8 T 细胞，DMOG 是缺氧诱导因子（HIFs）的稳定剂，诱导 HIF 与编码共刺激受体 CD81、GITR、OX40 和 4-1BB 的基因结合，导致其表达增加。DMOG 处理增加了 T 细胞对黑色素瘤细胞的杀伤作用，而用针对每个共刺激受体的激动性抗体进一步增强了这种杀伤作用。在荷瘤小鼠中，与使用对照 T 细胞和增加的肿瘤内 CD8 T 细胞（CD7、CD8A 和 CD8B1）、自然杀伤细胞（NCR1 和 KLRK1）和细胞毒性活性（穿孔素-1 和肿瘤坏死因子-α）标志物相比，使用体外用 DMOG 和激动性抗体处理的 T 细胞进行 ACT 可导致肿瘤生长减少。当用目前正在临床使用的三种高度选择性 HIF 稳定剂处理 CD8 T 细胞时，共刺激受体基因表达也被诱导。
