Lillian S. Wells Department of Neurosurgery, University of Florida, Gainesville, FL, USA.
Preston A. Wells, Jr. Center for Brain Tumor Therapy, University of Florida, Gainesville, FL, USA.
Nat Commun. 2024 Jul 12;15(1):5871. doi: 10.1038/s41467-024-49989-1.
There are numerous mechanisms by which glioblastoma cells evade immunological detection, underscoring the need for strategic combinatorial treatments to achieve appreciable therapeutic effects. However, developing combination therapies is difficult due to dose-limiting toxicities, blood-brain-barrier, and suppressive tumor microenvironment. Glioblastoma is notoriously devoid of lymphocytes driven in part by a paucity of lymphocyte trafficking factors necessary to prompt their recruitment and activation. Herein, we develop a recombinant adeno-associated virus (AAV) gene therapy that enables focal and stable reconstitution of the tumor microenvironment with C-X-C motif ligand 9 (CXCL9), a powerful call-and-receive chemokine for lymphocytes. By manipulating local chemokine directional guidance, AAV-CXCL9 increases tumor infiltration by cytotoxic lymphocytes, sensitizing glioblastoma to anti-PD-1 immune checkpoint blockade in female preclinical tumor models. These effects are accompanied by immunologic signatures evocative of an inflamed tumor microenvironment. These findings support AAV gene therapy as an adjuvant for reconditioning glioblastoma immunogenicity given its safety profile, tropism, modularity, and off-the-shelf capability.
胶质母细胞瘤细胞有许多逃避免疫检测的机制，这强调了需要策略性的联合治疗来实现明显的治疗效果。然而，由于剂量限制毒性、血脑屏障和抑制性肿瘤微环境，开发联合治疗方法具有挑战性。胶质母细胞瘤出奇地缺乏淋巴细胞，部分原因是缺乏促使淋巴细胞募集和激活所必需的淋巴细胞转运因子。在此，我们开发了一种重组腺相关病毒 (AAV) 基因治疗方法，该方法能够以 C-X-C 基序配体 9 (CXCL9) 为焦点和稳定地重建肿瘤微环境，CXCL9 是一种强大的淋巴细胞呼叫和接收趋化因子。通过操纵局部趋化因子的定向引导，AAV-CXCL9 增加了肿瘤浸润的细胞毒性淋巴细胞，使胶质母细胞瘤对女性临床前肿瘤模型中的抗 PD-1 免疫检查点阻断敏感。这些效应伴随着免疫特征，提示炎症肿瘤微环境。这些发现支持 AAV 基因治疗作为重塑胶质母细胞瘤免疫原性的辅助手段，因为其具有安全性、亲嗜性、模块化和现货能力。
