Department of Biomedical Engineering, ‡Institute for Nanobiotechnology, §Institute for Cell Engineering, and ∥Department of Pathology, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
ACS Nano. 2017 Jun 27;11(6):5417-5429. doi: 10.1021/acsnano.6b08152. Epub 2017 Jun 7.
We describe the development of a nanoparticle platform that overcomes the immunosuppressive tumor microenvironment. These nanoparticles are coated with two different antibodies that simultaneously block the inhibitory checkpoint PD-L1 signal and stimulate T cells via the 4-1BB co-stimulatory pathway. These "immunoswitch" particles significantly delay tumor growth and extend survival in multiple in vivo models of murine melanoma and colon cancer in comparison to the use of soluble antibodies or nanoparticles separately conjugated with the inhibitory and stimulating antibodies. Immunoswitch particles enhance effector-target cell conjugation and bypass the requirement for a priori knowledge of tumor antigens. The use of the immunoswitch nanoparticles resulted in an increased density, specificity, and in vivo functionality of tumor-infiltrating CD8+ T cells. Changes in the T cell receptor repertoire against a single tumor antigen indicate immunoswitch particles expand an effective set of T cell clones. Our data show the potential of a signal-switching approach to cancer immunotherapy that simultaneously targets two stages of the cancer immunity cycle resulting in robust antitumor activity.
我们描述了一种纳米颗粒平台的开发，该平台克服了免疫抑制性肿瘤微环境。这些纳米颗粒被两种不同的抗体包裹，这些抗体可以同时阻断抑制性检查点 PD-L1 信号，并通过 4-1BB 共刺激途径刺激 T 细胞。与单独使用可溶性抗体或与抑制性和刺激性抗体分别缀合的纳米颗粒相比，这些“免疫开关”颗粒显著延迟了多种体内小鼠黑色素瘤和结肠癌模型中的肿瘤生长并延长了生存时间。免疫开关颗粒增强效应靶细胞的连接，并绕过对肿瘤抗原的先验知识的要求。使用免疫开关纳米颗粒导致肿瘤浸润 CD8+T 细胞的密度、特异性和体内功能增加。针对单一肿瘤抗原的 T 细胞受体库的变化表明，免疫开关颗粒可扩展有效的 T 细胞克隆集。我们的数据表明，信号转换方法在癌症免疫治疗中具有潜力，该方法同时针对癌症免疫周期的两个阶段，从而产生强大的抗肿瘤活性。
