Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, Shenyang 110016, China.
Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
ACS Biomater Sci Eng. 2023 Jul 10;9(7):4108-4116. doi: 10.1021/acsbiomaterials.1c01637. Epub 2022 Jun 2.
OX40 (CD134, TNFRSF4) is a member of the tumor necrosis factor receptor superfamily that can be activated by its cognate ligand OX40L (CD252, TNFSF4) and functions as a pair of T cell costimulatory molecules. The interaction between OX40 and OX40L (OX40/OX40L) plays a critical role in regulating antitumor immunity, including promoting effector T cells expansion and survival, blocking natural regulatory T cells (T) activity, and antagonizing inducible T generation. However, current OX40 agonists including anti-OX40 monoclonal antibodies (aOX40) have serious side effects after systemic administration, which limits their clinical success and application. Herein, we propose a strategy to reprogram tumor cells into OX40L-expressing "artificial" antigen-presenting cells (APCs) by OX40L plasmid-loaded nanoparticles for boosting antitumor immunity in situ. A novel gene transfection carrier was prepared by a modular hierarchical assembly method, which could efficiently transfect various tumor cells and express OX40L proteins on their surface. These surface-decorated OX40L proteins were proved to stimulate T cell proliferation in vitro while stimulating strong antitumor immune responses in vivo. Importantly, this in situ reprogramming strategy did not induce any toxicity as observed in aOX40 treatment, thus providing a novel method for immune checkpoint stimulator application.
OX40（CD134、TNFRSF4）是肿瘤坏死因子受体超家族的成员，可被其配体 OX40L（CD252、TNFSF4）激活，并作为一对 T 细胞共刺激分子发挥作用。OX40 与 OX40L（OX40/OX40L）之间的相互作用在调节抗肿瘤免疫中起着关键作用，包括促进效应 T 细胞的扩增和存活、阻断天然调节性 T 细胞（Treg）的活性，以及拮抗诱导性 T 细胞的产生。然而，目前包括抗-OX40 单克隆抗体（aOX40）在内的 OX40 激动剂在全身给药后会产生严重的副作用，限制了它们的临床成功和应用。在此，我们提出了一种通过 OX40L 质粒负载的纳米颗粒将肿瘤细胞重编程为表达 OX40L 的“人工”抗原呈递细胞（APC）的策略，以在原位增强抗肿瘤免疫。采用模块化分层组装方法制备了一种新型基因转染载体，可有效转染各种肿瘤细胞，并在其表面表达 OX40L 蛋白。这些表面修饰的 OX40L 蛋白被证明可在体外刺激 T 细胞增殖，同时在体内刺激强烈的抗肿瘤免疫反应。重要的是，这种原位重编程策略不会像 aOX40 治疗那样引起任何毒性，从而为免疫检查点刺激剂的应用提供了一种新方法。
