肿瘤细胞治疗研究
英文原题：GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.
GPC3-targeted CAR-T cells expressing GLUT1 or AGK exhibit enhanced antitumor activity against hepatocellular carcinoma.
表达嵌合抗原受体的 T 细胞（CAR-T 细胞）可在血液系统恶性肿瘤患者中诱导强效抗肿瘤应答。
靶向 CD7 的嵌合抗原受体（CAR）T 细胞对血液系统恶性肿瘤应答强劲，但对肝细胞癌（HCC）等实体瘤疗效有限，部分原因是扩增和持久性不足。CD8+ T 细胞是适应性免疫应答的关键组成，在抗肿瘤免疫中发挥核心作用。活化 CD8+ T 细胞的主要代谢特征为有氧糖酵解；然而在肿瘤微环境中，肿瘤细胞和其他免疫抑制细胞大量摄取葡萄糖，会损害 T 细胞活化。只有当肿瘤微环境中的TIL（肿瘤浸润淋巴细胞）具有糖酵解优势时，T 细胞效应功能才可能被激活。葡萄糖转运蛋白 1（GLUT1）和酰基甘油激酶（AGK）分别可增强糖酵解代谢和活化 CD8+ T 细胞效应功能。本研究构建过表达 GLUT1 或 AGK 的 GPC3 靶向 CAR-T 治疗 HCC。过表达 GLUT1 或 AGK 的 GPC3 CAR-T 可在体外以抗原依赖方式特异、高效地裂解 GPC3 阳性肿瘤细胞。此外，GLUT1 或 AGK 过表达可保护 CAR-T 细胞在反复接触肿瘤细胞时免于凋亡。与第二代 CAR-T 相比，过表达 GLUT1 或 AGK 的 GPC3 靶向 CAR-T 在体内持久性更强，并在 HCC 同种移植小鼠模型中呈现更佳抗肿瘤作用。最后，研究揭示 GLUT1 或 AGK 可通过激活 PI3K/Akt 通路维持 CD8+ T 细胞抗凋亡能力。这一发现可能为晚期 HCC 提供治疗策略。
Chimeric antigen receptor-expressing T (CAR-T) cells induce robust antitumor responses in patients with hematologic malignancies. However, CAR-T cells exhibit only limited efficacy against solid tumors such as hepatocellular carcinoma (HCC), partially due to their limited expansion and persistence. CD8 + T cells, as key components of the adaptive immune response, play a central role in antitumor immunity. Aerobic glycolysis is the main metabolic feature of activated CD8 + T cells. In the tumor microenvironment, however, the uptake of large amounts of glucose by tumor cells and other immunosuppressive cells can impair the activation of T cells. Only when tumor-infiltrating lymphocytes (TILs) in the tumor microenvironment have a glycolytic advantage might the effector function of T cells be activated. Glucose transporter type 1 (GLUT1) and acylglycerol kinase (AGK) can boost glycolytic metabolism and activate the effector function of CD8 + T cells, respectively. In this study, we generated GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK for the treatment of HCC. GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK specifically and effectively lysed GPC3-positive tumor cells in vitro in an antigen-dependent manner. Furthermore, GLUT1 or AGK overexpression protected CAR-T cells from apoptosis during repeated exposures to tumor cells. Compared with second-generation CAR-T cells, GPC3-targeted CAR-T cells overexpressing GLUT1 or AGK exhibited greater CD8 + T-cell persistence in vivo and better antitumor effects in HCC allograft mouse models. Finally, we revealed that GLUT1 or AGK maintained anti-apoptosis ability in CD8 + T cells via activation of the PI3K/Akt pathway. This finding might identify a therapeutic strategy for advanced HCC.
MEMBER ACCOUNT
登录成功会直接打开下一页。
