Abstract
BACKGROUND: The immune tolerance of the tumor immune microenvironment (TIME) restricts the response to immune checkpoint inhibitors (ICIs). Targeted activation of dendritic cells (DCs) in the TIME seems to be a scheme for improving the therapeutic effect of ICIs treatment. The purpose of this study was to utilize nanotechnology to reprogram the immunosuppressive tumor immune microenvironment in situ, improving the response of ICIs to lung cancer. METHODS: In this study, a folic acid (FA)-modified nanoassembly (NA) loaded with low-dose paclitaxel (PTX) (FA-PTX NA), self-assembled by distearoylphosphatidylethanolamine-methoxy polyethylene glycol 2000-folic acid (DSPE-mPEG2000-FA) and PTX, was designed to reprogram the DC function of the TIME to sensitize cells to cancer immunotherapy. The characteristics of FA-PTX NAs were studied, and the cytotoxicity, cellular uptake, and DC stimulation of FA-PTX NAs were evaluated in vitro using a Lewis lung carcinoma (LLC) cell line and bone marrow-derived cells (BMDCs). Following this, the effect of the reprogrammed TIME and on the sensitization to immunotherapy in vivo were examined in a C57BL/6 mouse LLC subcutaneous xenograft model. RESULTS: The prepared FA-PTX NAs exhibited a slightly negative surface charge, appropriate size and shape, good drug release profiles, and high drug encapsulation efficiency and blood compatibility. The FA-PTX NAs were effectively uptaken by bone BMDCs, increasing the activation and expression of the costimulatory factor of BMDCs in vitro. In the LLC xenograft model treated with intravenous injection of FA-PTX NAs, the numbers of CD4(+) and CD8(+) T cells in the TIME increased significantly, the killing activity of tumor-specific cytotoxic T lymphocytes (CTLs) was significantly enhanced, and at the same time, the concentration of transforming growth factor β (TGF-β) decreased significantly. Furthermore, the infiltrated CD8(+) T cells in TIME were mainly distributed in the tumor parenchyma. The combination of FA-PTX NAs and ICIs effectively inhibited the growth of LLC xenograft tumor, demonstrating a greater effect than that of ICIs alone. Moreover, it was found that apoptosis induction, increase in CD4(+) and CD8(+) T-cell infiltration, and improvement in the distribution of CD8(+) T cells were involved in the anticancer mechanism of this combination treatment. CONCLUSIONS: The NA loaded with low-dose PTX can reprogram the DC function in the TIME and exert a synergistic anticancer effect with ICIs in lung cancer treatment. Increased sensitization to ICI therapy as stimulated by PTX-enhanced NAs has potential applications in lung cancer immunotherapy.