Nie Wen, Yu Ting, Liu Xiaoxiao, Wang Bilan, Li Tingting, Wu Yin, Zhou Xikun, Ma Lu, Lin Yunfeng, Qian Zhiyong, Gao Xiang
Department of Neurosurgery and Institute of Neurosurgery, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu, 610041, PR China.
Department of Medical Oncology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China.
Bioact Mater. 2021 Apr 6;6(11):3678-3691. doi: 10.1016/j.bioactmat.2021.03.031. eCollection 2021 Nov.
The immunosuppressive tumor microenvironment (TME) of cancer strongly hinders the anti-tumor immune responses, thereby resulting in disappointing responses to immunotherapy. Chemoattractive and promotive traits of chemokines exerted on leukocytes have garnered interest in improving the efficiency of immunotherapy by increasing the infiltration of immune cells in the TME. In this study, a folic acid (FA) -modified gene delivery system based on the self-assembly of DOTAP, MPEG-PCL-MPEG, and FA-PEG-PCL-PEG-FA, namely F-PPPD, was developed to deliver plasmids encoding the immunostimulating chemokine CKb11. The delivery of plasmid CKb11 (pCKb11) by F-PPPD nanoparticles resulted in the high secretion of CKb11 from tumor cells, which successfully activated T cells, suppressed the M2 polarization of macrophages, promoted the maturation of dendritic cells (DCs), facilitated the infiltration of natural killer (NK) cells and inhibited the infiltration of immunosuppressive cells in tumor tissues. Administration of F-PPPD/pCKb11 also significantly suppressed the cancer progression. Our study demonstrated a nanotechnology-enabled delivery of pCKb11, that remodeled the immunosuppressive TME, for cancer treatment.
癌症的免疫抑制性肿瘤微环境（TME）严重阻碍抗肿瘤免疫反应，从而导致免疫治疗效果不佳。趋化因子对白细胞的化学吸引和促进特性引发了人们通过增加免疫细胞在TME中的浸润来提高免疫治疗效率的兴趣。在本研究中，基于DOTAP、MPEG-PCL-MPEG和FA-PEG-PCL-PEG-FA的自组装开发了一种叶酸（FA）修饰的基因递送系统，即F-PPPD，用于递送编码免疫刺激趋化因子CKb11的质粒。F-PPPD纳米颗粒递送质粒CKb11（pCKb11）导致肿瘤细胞大量分泌CKb11，成功激活T细胞，抑制巨噬细胞的M2极化，促进树突状细胞（DCs）成熟，促进自然杀伤（NK）细胞浸润，并抑制肿瘤组织中免疫抑制细胞的浸润。给予F-PPPD/pCKb11也显著抑制了癌症进展。我们的研究证明了一种基于纳米技术的pCKb11递送方法，可重塑免疫抑制性TME用于癌症治疗。
