Enhanced cytotoxic T lymphocytes recruitment targeting tumor vasculatures by endoglin aptamer and IP-10 plasmid presenting liposome-based nanocarriers

• Published in: Theranostics 2019-01, Vol.9 (14), p.4066-4083
• Main Authors: Yang, Xiaomei, Zhao, Jing, Duan, Siliang, Hou, Xiaoqiong, Li, Xi, Hu, Zixi, Tang, Zhuoran, Mo, Fengzhen, Lu, Xiaoling
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; Apoptosis - physiology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Line; Cell Line, Tumor; Chemokine CXCL10 - genetics; Chemokine CXCL10 - metabolism; Electrophoretic Mobility Shift Assay; Endoglin - chemistry; Endothelial Cells - immunology; Endothelial Cells - metabolism; Female; Humans; Liposomes - chemistry; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Nude; Nanocapsules - chemistry; Plasmids - chemistry; Research Paper; Signal Transduction; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tumor Microenvironment - physiology
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.33383

: Adequate recruitment of highly active tumor antigen-specific cytotoxic T lymphocytes (CTLs) remains a major challenge in cancer immunotherapy. : To construct liposome (LP)-based nanocapsules with surface endoglin aptamer (ENG-Apt) encapsulating mouse interferon-inducible protein-10 (mIP-10), with the ability to target mouse tumor vascular endothelial cells (mTECs) and enhance CTLs targeting and recruitment to the tumor vasculature. : ENG-Apt/mIP-10-LP nanocapsules were prepared by grafting DSPE-PEG -ENG-Apt on the surface of liposomes containing mIP-10 plasmids, characterized and assessed for the cell binding specificity . The tumor-targeting ability of ENG-Apt/mIP-10-LP nanocapsules was evaluated . The anti-tumor efficacy of ENG-Apt/mIP-10-LP nanocapsules treatment, as well as the combination treatment of ENG-Apt/mIP-10-LP nanocapsules and adoptive TRP2CD8 T cells, were both tested in melanoma-bearing mice, by evaluation of the tumor volume and the mouse survival time. To discuss the anti-tumoral mechanism of ENG-Apt/mIP-10-LP nanocapsules-based therapies, IFN-γ secretion, proportion of TRP2CD8 T cells among TILs, MDSCs in the tumor microenvironment and Tregs in the spleen, were determined after the treatments. Proliferation and apoptosis of tumor cells, and tumor angiogenesis were also assessed. : The prepared ENG-Apt/mIP-10-LP nanocapsules possess an adequate nanometric size, good stability, high specificity to mTECs and tumor sites, along with the ability to induce mIP-10 expression and . Treatment of ENG-Apt/mIP-10-LP nanocapsules demonstrated CTLs enrichment into the tumor site, which inhibited tumor cell proliferation and angiogenesis, as well as promoted tumor-cell apoptosis, leading to a decrease in tumor progression and prolonged survival time in melanoma tumor-bearing mice. In addition, the proportion of MDSCs and Tregs was found to decrease. The combination of ENG-Apt/mIP-10-LP nanocapsules with adoptive TRP2CD8 T cells, showed stronger abilities in inhibiting tumor growth and increasing animal survival time, thereby displayed an enhanced anti-melanoma tumor efficacy, due to the recruitment of both endogenous CD8 T cells and exogenous TRP2CD8 T cells . : ENG-Apt/mIP-10-LP nanocapsules could enhance the recruitment of both endogenous and exogenous CTLs specifically targeting melanoma tumor vasculatures and exert anti-tumoral effect, therefore provides a potentially novel strategy for tumor immunotherapy.