Guangdong Cardiovsacular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Science, Guangzhou, 510080, China.
Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Science), Southern Medical University, Guangzhou, 510080, China.
Front Med. 2024 Aug;18(4):708-720. doi: 10.1007/s11684-024-1071-9. Epub 2024 Jun 4.
CD39 serves as a crucial biomarker for neoantigen-specific CD8 T cells and is associated with antitumor activity and exhaustion. However, the relationship between CD39 expression levels and the function of chimeric antigen receptor T (CAR-T) cells remains controversial. This study aimed to investigate the role of CD39 in the functional performance of CAR-T cells against hepatocellular carcinoma (HCC) and explore the therapeutic potential of CD39 modulators, such as mitochondrial division inhibitor-1 (mdivi-1), or knockdown CD39 through short hairpin RNA. Our findings demonstrated that glypican-3-CAR-T cells with moderate CD39 expression exhibited a strong antitumor activity, while high and low levels of CD39 led to an impaired cellular function. Methods modulating the proportion of CD39 intermediate (CD39)-phenotype CAR-T cells such as mdivi-1 and CD39 knockdown enhanced and impaired T cell function, respectively. The combination of mdivi-1 and CD39 knockdown in CAR-T cells yielded the highest proportion of infiltrated CD39 CAR-T cells and demonstrated a robust antitumor activity in vivo. In conclusion, this study revealed the crucial role of CD39 in CAR-T cell function, demonstrated the potential therapeutic efficacy of combining mdivi-1 with CD39 knockdown in HCC, and provided a novel treatment strategy for HCC patients in the field of cellular immunotherapy.
CD39 可作为新抗原特异性 CD8 T 细胞的重要生物标志物，与抗肿瘤活性和衰竭有关。然而，CD39 表达水平与嵌合抗原受体 T 细胞（CAR-T）功能之间的关系仍存在争议。本研究旨在探讨 CD39 在针对肝细胞癌（HCC）的 CAR-T 细胞功能表现中的作用，并探索 CD39 调节剂（如线粒体分裂抑制剂-1（mdivi-1））或通过短发夹 RNA 敲低 CD39 的治疗潜力。我们的研究结果表明，中等 CD39 表达的 Glypican-3-CAR-T 细胞具有强大的抗肿瘤活性，而高和低水平的 CD39 导致细胞功能受损。调节 CD39 中间（CD39）表型 CAR-T 细胞比例的方法，如 mdivi-1 和 CD39 敲低，分别增强和削弱 T 细胞功能。在 CAR-T 细胞中，mdivi-1 和 CD39 敲低的组合产生了最高比例的浸润性 CD39 CAR-T 细胞，并在体内表现出强大的抗肿瘤活性。总之，本研究揭示了 CD39 在 CAR-T 细胞功能中的关键作用，证明了 mdivi-1 与 CD39 敲低联合用于 HCC 的潜在治疗效果，并为细胞免疫治疗领域的 HCC 患者提供了一种新的治疗策略。
