Surface Modification of Macrophages with Nucleic Acid Aptamers for Enhancing the Immune Response against Tumor Cells

摘要

Antigen-presenting cells play a dominant role in cancer immunotherapy. Tumor cells, however, can still resort to several mechanisms of immune evasion that ultimately lead to the development of tumor tissues. In the current study, we performed surface modification of live macrophages with nucleic acid aptamers with the aim to enhance their affinity for tumor cells. Intercellular adhesion of tumor cells to surface-modified macrophages and the functions of the macrophages when in contact with tumor cells were investigated. To immobilize thiol-terminated nucleic acid aptamers that showed high affinity for the membrane protein of the tumor cells, methacryloyl groups were delivered into the sialic acids of the macrophages via metabolic glycoengineering (MGE). The proposed surface modification was cytocompatible and did not induce any undesirable activation of macrophages. According to the cell proliferation assay, the density of aptamers immobilized on a macrophage was found to decrease over time. However, the presence of aptamers on the cell surface was observed for more than 24 h after the immobilization. The number of adherent tumor cells on aptamer-immobilized macrophages was significantly larger than that of non-immobilized macrophages. Although the number of adherent tumor cells on aptamer-immobilized macrophages was not influenced by the pretreatment of doxorubicin to induce apoptosis in tumor cells, the apoptosis-induced tumor cells were highly phagocytosed by the aptamer-immobilized macrophages. The secretion amount of proinflammatory cytokines (TNF-alpha and IL-12) from the macrophages was coincident with the phagocytic index, which increased with the phagocytic uptake of tumor cells by the macrophages. In addition, the expression level of the major histocompatibility complex (MHC) class I and II molecules, required for antigen presentation, increased in nucleic acid aptamer-immobilized macrophages. Overall, the surface modification of macrophages with nucleic acid aptamers improved the tumor cell recognition of macrophages, indicating that the combination of cell surface engineering and anticancer drug treatment could constitute a promising strategy for tumor cell elimination.