肿瘤细胞治疗研究
英文原题：Pharmacologic HIF stabilization activates costimulatory receptor expression to increase antitumor efficacy of adoptive T cell therapy.
过继性细胞转移（ACT）是一种增强抗肿瘤免疫的治疗策略。
过继性细胞转移（ACT）是一种增强抗肿瘤免疫的治疗策略。在此，我们报告，用二甲基草酰甘氨酸（DMOG）——一种缺氧诱导因子（HIFs）的稳定剂——体外处理小鼠 CD8+ T 细胞，可诱导 HIF 与编码共刺激受体 CD81、GITR、OX40 和 4-1BB 的基因结合，从而导致表达增加。DMOG 处理增强了 T 细胞对黑色素瘤细胞的杀伤，而靶向每种共刺激受体的激动剂抗体进一步增强了这种杀伤。在荷瘤小鼠中，与使用对照 T 细胞的 ACT 相比，使用经 DMOG 和激动剂抗体体外处理的 T 细胞进行 ACT 导致肿瘤生长减少，并增加了瘤内 CD8+ T 细胞标志物（CD7、CD8A 和 CD8B1）、NK 细胞标志物（NCR1 和 KLRK1）以及细胞溶解活性标志物（穿孔素-1 和肿瘤坏死因子-α）的表达。当用目前临床使用的三种高选择性 HIF 稳定剂处理 CD8+ T 细胞时，共刺激受体基因表达也被诱导。
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.
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