Renji-Med-X Clinical Stem Cell Research Center, Renji Hospital, School of Medicine and School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China; Med-X Research Institute, Shanghai Jiao Tong University, Shanghai, China.
Department of Obstetrics and Gynecology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Int Immunopharmacol. 2024 Jan 5;126:111249. doi: 10.1016/j.intimp.2023.111249. Epub 2023 Nov 22.
Stimulation of costimulatory receptors serves as an alternative immunotherapeutic strategy other than checkpoint inhibition. However, systemic administration of the agonistic antibodies is associated with severe toxicities, which is one of the major obstacles for their clinical application. This study aimed to develop a mesenchymal stem cell (MSC)-based system for tumor-targeted delivery of TNF superfamily ligands and assess their potential in enhancing antitumor immunity. Here we established an MSC-based system for tumor-targeted delivery of TNF superfamily ligands, including TNFSF4, 9 and 18. The TNFSF receptors (TNFRSFs) were evaluated in mouse models and patient samples for lung and colorectal cancers. TNFRSFs were all expressed at various levels on tumor-infiltrated lymphocytes, with TNFRSF18 being the most prevalent receptor. Human umbilical cord-derived MSCs expressing these costimulatory ligands (MSC-TNFSFs) effectively activated lymphocytes in vitro and elicited antitumor immunity in mice. TNFSF4 showed the least antitumor efficacy in both LLC1 and CT26 tumor models. MSC-TNFSF9 showed the most potent tumor-inhibiting effect in the LLC1 tumor model, while MSCs expressing TNFSF18 in combination with CXCL9 most significantly repressed CT26 tumor growth. Overall, TNFSF9 and TNFSF18 exhibited stronger lymphocyte-stimulating and antitumor activities than TNFSF4. Our study provides evidence that antitumor effects of agonism of different costimulatory receptors may vary in different tumor types and presents a promising approach for targeted delivery of TNF superfamily costimulatory ligands to avoid the systemic toxicities and side effects associated with immune agonist antibodies.
刺激共刺激受体是一种替代检查点抑制的免疫治疗策略。然而，激动性抗体的全身给药与严重的毒性有关，这是其临床应用的主要障碍之一。本研究旨在开发一种基于间充质干细胞（MSC）的系统，用于肿瘤靶向递送达 TNF 超家族配体，并评估其增强抗肿瘤免疫的潜力。本研究建立了一种基于 MSC 的系统，用于肿瘤靶向递送达 TNF 超家族配体，包括 TNFSF4、9 和 18。在肺癌和结直肠癌的小鼠模型和患者样本中评估了 TNFSF 受体（TNFRSFs）。TNFRSFs 在肿瘤浸润淋巴细胞上以不同的水平表达，其中 TNFRSF18 是最常见的受体。表达这些共刺激配体的人脐带间充质干细胞（MSC-TNFSFs）在体外有效地激活淋巴细胞，并在小鼠中引发抗肿瘤免疫。TNFSF4 在 LLC1 和 CT26 肿瘤模型中均显示出最低的抗肿瘤功效。MSC-TNFSF9 在 LLC1 肿瘤模型中显示出最强的肿瘤抑制作用，而表达 TNFSF18 与 CXCL9 的 MSC 则最显著地抑制 CT26 肿瘤生长。总体而言，TNFSF9 和 TNFSF18 比 TNFSF4 表现出更强的淋巴细胞刺激和抗肿瘤活性。本研究提供了证据表明，不同共刺激受体的激动作用在不同的肿瘤类型中可能具有不同的抗肿瘤效果，并提出了一种有前途的方法，用于靶向递送达 TNF 超家族共刺激配体，以避免与免疫激动抗体相关的全身毒性和副作用。
