TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM.
TIGIT and PD-1 dual checkpoint blockade enhances antitumor immunity and survival in GBM.
复制标题
DOI：
10.1080/2162402x.2018.1466769
复制
发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Lim M
中科院分区：
文献类型：
--
作者：
Hung AL;Maxwell R;Theodros D;Belcaid Z;Mathios D;Luksik AS;Kim E;Wu A;Xia Y;Garzon-Muvdi T;Jackson C;Ye X;Tyler B;Selby M;Korman A;Barnhart B;Park SM;Youn JI;Chowdhury T;Park CK;Brem H;Pardoll DM;Lim M
已经在临床前和临床环境中研究了抑制性检查点阻断在胶质母细胞瘤治疗中的应用。 TIGIT 是最近发现的一种新型检查点抑制剂，在癌症免疫中发挥作用。在这项研究中，我们试图确定抗 PD-1 和抗 TIGIT 联合疗法对小鼠胶质母细胞瘤 (GBM) 模型生存的影响，并阐明潜在的免疫机制。使用患有颅内 GL261-luc+ 肿瘤的小鼠，我们发现与引流颈淋巴结 (CLN) 和脾脏相比，大脑中 CD8+ 和调节性 T 细胞 (Treg) 的 TIGIT 表达上调。然后我们证明，与对照组和单一治疗组相比，使用抗 PD-1 和抗 TIGIT 双重疗法可显着提高生存率。治疗效果与效应 T 细胞功能的增强以及抑制性 Tregs 和肿瘤浸润树突状细胞 (TIDC) 的下调相关。临床上，患者 GBM 样本中肿瘤浸润淋巴细胞上的 TIGIT 表达升高，表明 TIGIT 通路可能是一个有价值的治疗靶点。 TIGIT 配体 PVR 的表达进一步预示着低级别神经胶质瘤患者的生存结果不佳。我们得出的结论是，当与抗 PD-1 联合使用时，抗 TIGIT 是针对小鼠 GBM 的有效治疗策略，通过修改 T 细胞和骨髓区室来提高总体生存率。鉴于 PVR 在人类 GBM 细胞上表达的证据，TIGIT 是治疗这些患者的一个有前途的免疫治疗靶点。
The use of inhibitory checkpoint blockade in the management of glioblastoma has been studied in both preclinical and clinical settings. TIGIT is a novel checkpoint inhibitor recently discovered to play a role in cancer immunity. In this study, we sought to determine the effect of anti-PD-1 and anti-TIGIT combination therapy on survival in a murine glioblastoma (GBM) model, and to elucidate the underlying immune mechanisms. Using mice with intracranial GL261-luc+ tumors, we found that TIGIT expression was upregulated on CD8+ and regulatory T cells (Tregs) in the brain compared to draining cervical lymph nodes (CLN) and spleen. We then demonstrated that treatment using anti-PD-1 and anti-TIGIT dual therapy significantly improved survival compared to control and monotherapy groups. The therapeutic effect was correlated with both increased effector T cell function and downregulation of suppressive Tregs and tumor-infiltrating dendritic cells (TIDCs). Clinically, TIGIT expression on tumor-infiltrating lymphocytes was shown to be elevated in patient GBM samples, suggesting that the TIGIT pathway may be a valuable therapeutic target. Expression of the TIGIT ligand, PVR, further portended a poor survival outcome in patients with low-grade glioma. We conclude that anti-TIGIT is an effective treatment strategy against murine GBM when used in combination with anti-PD-1, improving overall survival via modifications of both the T cell and myeloid compartments. Given evidence of PVR expression on human GBM cells, TIGIT presents as a promising immune therapeutic target in the management of these patients.